Download katp channels in the cardiovascular system

Physiol Rev 96: 177–252, 2016
Published December 9, 2015; doi:10.1152/physrev.00003.2015
KATP CHANNELS IN THE CARDIOVASCULAR
SYSTEM
Monique N. Foster and William A. Coetzee
Departments of Pediatrics, Physiology & Neuroscience, and Biochemistry and Molecular Pharmacology, NYU
School of Medicine, New York, New York
L
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
X.
XI.
THE ROAD TO THE DISCOVERY OF...
PROPERTIES OF CARDIOVASCULAR...
THE PROTEIN SUBUNIT COMPOSITION...
MOLECULAR MECHANISMS THAT...
SYNTHESIS, TRAFFICKING, AND...
THE PHARMACOLOGY OF KATP...
DIFFERENT SUBTYPES OF KATP...
CARDIOVASCULAR PHENOTYPES OF...
PATHOPHYSIOLOGICAL ROLES OF...
GENETIC VARIATION IN KATP CHANNEL...
CONCLUSIONS
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228
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I. THE ROAD TO THE DISCOVERY OF KATP
CHANNELS
Since the first use of the voltage-clamp technique in cardiac
tissue in 1964 (172), the description of the ionic nature of
cardiac excitation was riddled with problems and artifacts, in
part due to technical limitations of the recording equipment,
such as the two-microelectrode and sucrose gap voltage-clamp
techniques, and partly due to the complexity and multicellular
nature of cardiac tissue (57). Two events coincided in the early
1980s that greatly accelerated the pace of cardiac electrophysiological discovery. The first was the successful isolation of
enzymatically isolated, Ca2⫹-tolerant cardiac myocytes (96,
187, 643), and the second was the Nobel prize winning description of the tight-seal, single-electrode patch-clamp technique (316, 742). Subsequent progress was rapid, and many
new discoveries were made, for example, a description of
Ca2⫹ channels and their regulation by cAMP (102) and a
description of a acetylcholine-activated K⫹ channel in nodal
tissue (683). Other new advances in the early 1980s included
the finding in the laboratory of Edward Carmeliet that metabolic inhibition by dinitrophenol (DNP) led to action potential
shortening of isolated ventricular myocytes, due to activation
of a time-independent outward K⫹ current (379, 832). This
finding verified prior observations by the same group using
conventional approaches made in multicellular preparations
(radioactive flux studies and two-electrode voltage clamping),
demonstrating that hypoxia induces K⫹ fluxes and an outward K⫹ current that are responsible for the action potential
shortening (845, 848-850). The descriptions of the sarcolemmal/plasmalemmal ATP-sensitive K⫹ channel in ventricular
myocytes by Noma (607) and Trube and Hescheler (815) gave
unique insights into the unitary channel events that underlie
this metabolically active outward K⫹ current. KATP channels
have subsequently been found in most other tissue types, and
we know that they have diverse roles in human physiology and
pathophysiology (22). KATP channels have subsequently also
been found in the inner membrane of mitochondria (376). For
simplicity, throughout this review, we will refer to the class of
sarcolemmal/plasmalemmal channels as “KATP channels,”
and those in the mitochondria will be referred to as mitochondrial KATP channels.
Diverse classes of KATP channels exist, which differ significantly from each other in different tissues and cell types in
terms of their nucleotide sensitivities, their biophysical
properties, and their sensitivities to pharmacological agents
(some examples are shown in TABLES 1–3). The various
subtypes of KATP channels originate in part from the assembly from specific combinations of the various Kir6.x and
0031-9333/16 Copyright © 2016 the American Physiological Society
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Foster MN, Coetzee WA. KATP Channels in the Cardiovascular System. Physiol Rev 96:
177–252, 2016. Published December 9, 2015; doi:10.1152/physrev.00003.2015.—
KATP channels are integral to the functions of many cells and tissues. The use of electrophysiological methods has allowed for a detailed characterization of KATP channels in terms
of their biophysical properties, nucleotide sensitivities, and modification by pharmacological
compounds. However, even though they were first described almost 25 years ago (Noma 1983, Trube
and Hescheler 1984), the physiological and pathophysiological roles of these channels, and their
regulation by complex biological systems, are only now emerging for many tissues. Even in tissues
where their roles have been best defined, there are still many unanswered questions. This review aims
to summarize the properties, molecular composition, and pharmacology of KATP channels in various
cardiovascular components (atria, specialized conduction system, ventricles, smooth muscle, endothelium, and mitochondria). We will summarize the lessons learned from available genetic mouse
models and address the known roles of KATP channels in cardiovascular pathologies and how genetic
variation in KATP channel genes contribute to human disease.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Table 1. KATP channel subunit genes
Protein
Gene
Kir6.1
Kir6.2
SUR1
SUR2
KCNJ8
KCNJ11
ABCC8
ABCC9
Potassium inwardly rectifying channel, subfamily J, member 8
Potassium inwardly rectifying channel, subfamily J, member 11
ATP-binding cassette, subfamily C (CFTR/MRP), member 8
ATP-binding cassette, subfamily C (CFTR/MRP), member 9
Exons
12p11.23
11p15.1
11p15.1
12p12.1
3
1
40
40
The regulation of KATP channels at the protein and molecular level is dealt with in section IV. For description of the
regulation of KATP channels by receptor signaling pathways, please refer to a recent review (806).
A. Intracellular ATP Blocks the KATP
Channel
A defining characteristic of KATP channels is that their open
probability is vastly decreased in the presence of ATP at the
cytosolic face of an excised membrane patch (416, 607, 815)
⫹
(FIGURE 1). Other types of K channels are mostly insensitive
to cytosolic ATP, but certain types of K⫹ channels are activated by cytosolic ATP, such as the members of the renal Kir1
subfamily (e.g., the ROMK1 channel) and members of the
retinal Kir4 subfamily (353, 784). For KATP channels, an
inverse relationship exists between the channel’s opening
probability and the ATP concentration, which can be
described by a modified Hill equation (432). In the initial
studies performed with inside-out membrane patches obtained from cardiac ventricular myocytes, the ATP concentration needed to produce half-maximal block was
⬃100 ␮M (607). The channel can also be blocked by
nonhydrolyzable ATP analogs or in the absence of Mg2⫹,
demonstrating that ATP hydrolysis is not required for
channel block (23, 135, 416, 486). For example, AMPPNP, AMP-PCP, and ATP␥S (909) effectively block KATP
channels from cardiac ventricular myocytes and pancre-
II. PROPERTIES OF CARDIOVASCULAR
KATP CHANNELS
The following text is mainly focused on the KATP channel of
the ventricular muscle, which has properties that are better
characterized than the KATP channels in most other cardiovascular tissue types. Where possible, the ventricular KATP
channels are compared with KATP channels in other cardiovascular tissues such as the atria, the specialized cardiac
conduction system, the endothelium, the coronary vascular
smooth muscle, and the mitochondria. For a more detailed
description of these channels, please refer to section VII.
Table 2. Diverse properties (and molecular composition) of KATP channels found in cardiovascular different tissue types and in
mitochondria
Tissue
Conductance, pS
ATP IC50, ␮M
Ventricle
Conduction system
Atrium
75–85 (48, 607)
52–60 (48, 318, 502)
52–80 (50, 342, 383,
833, 945)
15–25 (163, 565)*
25–40 and 150 (390, 426,
618, 851)
15–100 (54, 153)
21–100 (48, 486, 500, 607)
116–119 (48, 502)
39–100 (50, 945)
Kir6.2/SUR2A (38)
Kir6.1/Kir6.2/SUR2B (48)
Kir6.2/SUR1/SUR2A (50, 90, 237, 678)
29–200 (649)
ND
Kir6.1/SUR2B (371, 374)
Kir6.1/Kir6.2/SUR2B (705, 907)
800 ␮M (153, 376)
Kir1.1 and/or SUR2A-55 (240, 901)
Smooth muscle
Endothelium
Mitochondria
Subunit Composition
ND, no data. *Two classes of vascular smooth muscle channels having been described with small/medium
(7–15 pS) or large (20 –25 ps) conductances (649). There is evidence that NDPs (e.g., GDP, ADP, UDP) are
required for channel activation, and vascular channels are sometimes referred to as KNDP channels (56).
Reference numbers are given in parentheses.
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SURx subunits. For example, sarcolemmal KATP channels
in striated muscle and those in pancreatic ␤-cells have the
same pore-forming subunit (Kir6.2), but differ in the use of
the regulatory subunit (SUR2A in the case of the ventricular
channel and SUR1 in the pancreas). Smooth muscle KATP
(or KNDP) channels, in contrast, appear to be composed of
Kir6.1 subunits in combination with SUR2B subunits
(721). The mitochondrial KATP channels are also sensitive
to ATP and antidiabetic sulfonylureas. They are important
in the setting of ischemia/reperfusion (291), but their molecular composition is only now being defined. The focus of
this treatise is to review the properties of cardiovascular
KATP channels and attempt to provide an impartial summary of the literature and views related to the roles for these
channels in cardioprotection.
Chromosome
KATP CHANNELS IN CARDIOPROTECTION
Table 3. Pharmacological compounds affecting KATP channel opening
Target
Pinacidil
Glibenclamide
HMR-1098
Diazoxide
Tolbutamide
5-Hydroxydecanoate
Ventricular KATP
channels
4–30 ␮M (246,
758)
8–480 nM (229,
271, 462)
0.2–0.9 ␮M (271,
410, 539)
54–500 ␮M (48,
213, 262, 642)
Needs cytosolic
ADP1
380–1,000 ␮M
(63, 842)
Atrial KATP
channel
⬃5–30 ␮M (452,
695)
1.2 nM (50) to ⬃3
␮M (695)
0.9 ␮M (271)5
0.1 nM to ⬃130 ␮M
(50, 237, 452,
642, 922)2
⬍100 ␮M (833) or
1.3 mM (945)
ND
Conduction
system KATP
channel
2.6 ␮M (758)
2.6 ␮M (271)5
⬍200 ␮M (48)
⬍200 ␮M (48)
ND
Smooth muscle
KNDP channel
0.5–1 ␮M (246,
641, 758)
⬍20 ␮M (334)
7–37 ␮M (535,
594, 641, 648)
351 ␮M (648)
ND
⬍0.1 or ⬍300 ␮M
(478, 705, 868)
224 ␮M (426)
ND
Endothelial KATP
channel
ND
25 nM (246)
ND
ND
0.2–100 ␮M
(497, 608, 609)
or no effect (552)
⬃40–365 ␮M
(355, 489)
1–6 ␮M (386)
⬎100 ␮M (512)
0.4–27 ␮M (261,
263, 512, 876)3
⬎100 ␮M4
45–100 ␮M (386,
512) or no effect
(113)
Pancreatic ␤-cell
KATP channel
⬎500 ␮M (24)
4–9 nM (271, 946)
720 ␮M (539)
7–100 ␮M (24,
816, 946)
4–20 ␮M (24,
946)
10 nM to 500 ␮M
(389)6
Kir6.x/SUR1
⬎1 mM (246,
312)
4.2 nM (288)
3–33 ␮M (512, 921)
or 860 ␮M (539)
10 ␮M (512)
5 ␮M and 2 mM
(288)
⬃100 ␮M (512)
Kir6.1/SUR2B
2 ␮M (731)
0.3 ␮M (186)
ND
30–60 ␮M (372,
512)
25 ␮M (186)
ND
Kir6.2/SUR2A
10 ␮M (731)
27 nM (288)
2–100 ␮M (539,
921)
⬎100 ␮M (512).
Needs cytosolic
ADP (151, 546)
280 ␮M (186) or
1.7 mM (288)
ND
Blocks Ito,
IKur and ICl, cAMP;
IC50 ⬃30–76 ␮M
(700, 809), blocks
glycolysis (62)
Blocks mitochondrial
effects induced by
KCOs (403)
SDH inhibition: 32–
49 ␮M (196,
699)
Uncouples oxidative
phosphorylation
(428),
stimulates
glucose oxidation
(461)
Off-target effects Uncouples
mitochondrial
oxidative
phosphorylation
(773)
5-HD is a substrate
for mitochondria
(320, 321)
Data are K1/2 values. References numbers are given in parentheses. ND, no data; SDH, succinate
dehydrogenase; KCO, KATP channel opener. 1Changes in intracellular nucleotide concentrations may make
the ventricular KATP channel more susceptible to activation by diazoxide. For example, diazoxide (300 ␮M)
has little effect on the ventricular Kir6.2/SUR2A channel, but increases currents 3 times in the presence
of 100 ␮M cytosolic ADP (151). 2The large range reported for diazoxide sensitivity and molecular
composition of atrial KATP channels may be due to differences in age or species. For example, mouse atrial
KATP channels may have an SUR1 component (237), while this may not be the case for human atria based
on diazoxide-sensitivity experiments (222). 3Effects may be variable. In one study, no activation of mitochondrial KATP channel was reported by up to 500 ␮M diazoxide (153). Some studies failed to find KATP
channels in the mitochondrial inner membrane (17, 91). 4Studies on the direct effects of tolbutamide on
mitoKATP channel are sparse. Diazoxide-induced flavoprotein oxidation of cardiomyocytes was reported to
be unaffected by 100 ␮M tolbutamide (692). 5Data are for HMR-1883, which is a lipophilic derivative of
HMR-1098. 6Effects of 5 -HD are complex, inhibiting the KATP channel at low concentrations but activated
channels at higher concentrations.
atic ␤-cells (23, 416, 613). Other nucleotides also inhibit
KATP channel activity, but less efficiently. For example,
the block by free ADP is ⬃10 –20 times less potent than
that of ATP (23, 486, 754). Other nucleotides (e.g., CTP,
GTP, ITP, or AMP) are even less effective (486, 754). In
the cardiovascular system, the ATP sensitivity is higher in
the atrium and ventricle than some other tissues (IC50
value: ventricle ⬃ atrium ⬍ smooth muscle ⬍ conduction
system ⬍⬍ mitochondria; TABLE 2).
B. MgADP Stimulates KATP Channel
Activity: Regulation by the ATP/ADP
Ratio
Although free ADP can block the KATP channel (albeit
less effectively than ATP; see above), it became apparent
that Mg2⫹ modulates the channel=s response to ADP. In
the “open” cell-attached configuration, in which the cell
is permeabilized by a brief exposure to saponin (in an
attempt not to disrupt the cytosolic milieu, as would be
the case with whole-cell recordings), MgADP was found
to stimulate KATP channel opening (194) (FIGURE 2). This
stimulation was not observed with AMP, cAMP, or adenosine. The nonhydrolyzable ADP analog ADP␤S did not
stimulate KATP channel activity, suggesting the involvement of phosphorylation processes. This experiment
gave rise to the concept that the physiological control of
KATP channel opening is mediated by changes in the ATP/
ADP ratio, rather than solely by ATP (194). Subsequent
experiments demonstrated that the stimulatory effects of
ADP is Mg2⫹-dependent (227, 486), which gave further
credence to the notion that phosphorylation and/or hydrolysis processes are involved.
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Mitochondrial
KATP channel
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
+80mV
K+
ATP
Inside-out patch
0
5 pA
200 ms
0
C. AMP Stimulates KATP Channel Activity
and Surface Expression
AMP, rather than ADP, is increasingly being recognized as
the key regulatory molecule for sensing changes in energy
metabolism and for regulating metabolic pathways (325).
Intracellular AMP levels are almost undetectably low in
+
–
+
AMPK
+
ATP
ADP
AMP
FIGURE 2. Regulation of KATP channels by intracellular nucleotides. The sarcolemmal/plasmalemmal KATP channel is a heterooctameric complex of four Kir6.x and four SURx subunits (respectively color coded in blue and orange). Channel activity is inhibited by
intracellular ATP, with an IC50 value ranging between 20 and 800
␮M ATP (TABLE 2). In the presence of MgATP, ADP stimulates
KATP channel opening, such that the channel is regulated by the
ADP-to-ATP ratio. Even a small decrease in ATP levels during metabolic stress translates to a relatively large increase in AMP levels,
which may indirectly further stimulate KATP channel opening and
promote surface trafficking through the actions of the trimeric AMPactivated protein kinase (AMPK) and adenylate kinase.
180
normal well-oxygenated heart tissue due to the action of
adenylate kinase, which interconverts ATP, ADP, and AMP
and maintains their concentrations close to equilibrium according to this reaction:
ATP ⫹ AMP ↔ 2 ADP
In well-oxygenated cells, the AMP levels are kept at very
low levels since this reaction operates from right to left,
ensuring an ADP/ATP ratio of ⬃1:10 and an AMP/ATP
ratio, which varies as the square of the ADP:ATP ratio, of
⬃1:100 (327). When ATP consumption exceeds production during cellular stress, the ADP/ATP ratio rises, but the
AMP/ATP ratio rises much more. For example, for a 5-fold
increase of the ADP/ATP ratio, the AMP/ATP ratio will rise
25-fold (327). Thus the intracellular AMP concentration
changes much more dramatically than that of ATP or ADP.
Evolution has adapted to monitor changes in cellular energy
status by responding to changes in AMP levels, for example,
by activating AMP-activated protein kinase (AMPK),
which has been described as the “fuel gauge of the mammalian cell” (326). Although AMP does not directly regulate
KATP channel opening (607), there is now evidence that
AMP-dependent activation of AMPK increases ventricular
KATP channel open probability (905) and, similar to the
situation in pancreatic ␤-cells (109, 632), enhances KATP
channel surface density through trafficking mechanisms
(767, 824). AMP may also participate in phosphotransfer
reactions that are mediated by adenylate kinase to regulate
the ADP/ATP ratio in the immediate vicinity of the channel
to stimulate KATP channel opening (100). Thus, even
though the action is indirect, elevated AMP levels during
cellular stress function to stimulate KATP channel function
(FIGURE 2).
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FIGURE 1. Electrophysiological recordings of cardiac ventricular KATP channels.
KATP channel activity recorded from an enzymatically isolated mouse ventricular myocyte. The recording was made in the insideout configuration. The top trace shows currents recorded in the absence of ATP, and
the bottom trace depicts current recordings after the application of 1 mM ATP to
the cytosolic face of the membrane. The
pipette potential was ⫹80 mV, which corresponds to a membrane potential of ⫺80
mV. Upward current deflections depict inward current.
KATP CHANNELS IN CARDIOPROTECTION
D. Phosphorylation Is Required for
Maintained KATP Channel Activity
E. KATP Channels Exhibit Weak Inward
Rectification Properties
Many K⫹ channels are regulated by voltage and/or Ca2⫹
and are referred to as Kv or KCa channels (126). A group of
K⫹ channels that is not regulated in this manner is referred
to as inward rectifier K⫹ (Kir) channels, with the name due
to the rectification properties and the shape of their currentvoltage relationships. The Kir channels can be arbitrarily
divided into a class with strong inward rectification properties or weak rectifiers, which exhibit larger outward currents upon membrane depolarization. KATP channels are
members of the latter group (596). We will discuss the
mechanisms of inward rectification in section IV.
III. THE PROTEIN SUBUNIT COMPOSITION
OF KATP CHANNELS
A. Terminology
Historically, the word channel refers to an ion conduction
pathway (60), and its use in electrophysiology may have
originated with the German word Kanäle, which means a
“watercourse” or a “pipe.” By this definition, a “channel”
(e.g., KATP channel) is an electrophysiological entity. A subunit is a biochemical entity and is a component of the protein complex that gives rise to channel function (e.g., Kir6.2
subunit) and a gene is the DNA that codes for the subunit
(e.g., KCNJ11 gives rise to the Kir6.2 subunit) (TABLE 1). It
B. Pore-Forming Subunits
Topologically, the Kv and KCa channels consist of protein
subunits that span the membrane with six (or seven in the
case of the BK channel=s subunit, KCa3.1) ␣-helixes (126).
The Kir family of subunits, in contrast, consists of proteins
with two membrane-spanning ␣-helixes (126, 597) (FIGURE
3A). Protein subunits of channels in the Kir family are
grouped in several subfamilies (Kir1 to Kir7), with one or
more paralogs within each subfamily (e.g., Kir3.1 to
Kir3.4). Members of two of these subfamilies (Kir1 and
Kir6) have been implicated as being the pore-forming subunits of KATP channels (FIGURES 4 AND 5).
1. Kir1.1 subunits
Not long after the identification of molecular components
of voltage-gated K⫹ channels using molecular cloning
methods (418, 631, 765, 785, 798), there was much excitement when the first subunit of an inward rectifier K⫹ channel (Kir1.1 or ROMK1; from the KCNJ1 gene) was identified by expression cloning using poly(A)⫹ RNA isolated
from the outer medulla of rat kidneys (353). ROMK1 channel opening requires the presence of MgATP, but not
Na2ATP, demonstrating the involvement of phosphorylation processes (554). ROMK1 is generally functionally associated with K⫹ fluxes in the kidney (860). In contrast to
MgATP, Na2ATP at concentrations less than 10 mM has
little effect on the activity of either the Kir1.1 channel expressed in oocytes (555) or the native kidney KATP channel
(859). MgATP binds to the Kir1.1 COOH terminus with
high affinity, e.g., TNP-ATP binding occurs with a Kd of ⬇3
␮M (836). Although activated by MgATP, there is evidence
that MgATP at high concentrations can block Kir1.x channels, with ROMK2 being more sensitive to ATP block (with
an IC50 of ⬃5 mM) than ROMK1 (555). Consistent for a
major role of Kir1.1 channels in the kidney, KCNJ1 mutations in humans are associated with Bartter syndrome
(340), which is characterized by salt wasting, hypokalemic
alkalosis, hypercalciuria, and a low blood pressure. Several
mRNA splice variants have been described, giving rise to
multiple protein variants (ROMK1 to ROMK6) (58, 72,
455). ROMK2 (or Kir1.1b) is a splice variant of Kcnj1,
which is a subunit with a truncated NH2 terminus. It has
been identified by expression cloning using poly(A)⫹ RNA
from whole rat kidney and has a single-channel conductance of 30 –36 pS (110, 930). As is the case for many
inward rectifier K⫹ channels (126), the channel comprised
of Kir1.1b is highly selective for K⫹ and is blocked by Rb⫹
and Ba2⫹. It is also blocked by oxidizing agents (244) and is
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In one of the earliest recordings of KATP channels from
inside-out patches of ventricular myocytes, it was noted
that many KATP channels becomes inactive within 5 min
after patch excision (815). This phenomenon, referred to as
“rundown” of KATP channels, was found paradoxically to
be partially prevented (or even reversed) by MgATP, but
not by AMP-PNP, ATP␥S, or ATP in the absence of Mg2⫹
(226, 231, 613). This result suggested that phosphorylation
processes are involved in maintaining channel activity following patch excision (822). Interestingly, the presence of
the divalent cation Ca2⫹ on the cytosolic face of the membrane powerfully inactivates the KATP channel (or induces
rundown) (226), and Ca2⫹-dependent inactivation can be
restored by MgATP. Since the MgATP-dependent recovery
is inhibited by wortmannin (884), it is believed that loss of
specific phospholipids in the membrane after patch excision
is partly responsible for the rundown process. It is not clear
to what extent the rundown process is an experimental
artifact or whether it has physiological implications. Nevertheless, these studies have contributed to our understanding of the role of specific inositolphoshate products in the
regulation of KATP channel function (see sect. IVF).
has, however, become colloquial to use these terms interchangeably by referring to a channel as the ionic current,
the protein, the mRNA, or even the gene. We will attempt to
follow the traditional convention, but also use the shorthand notation (e.g., Kir6.2 channel).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
A
Voltage-gated K+ channels
Ca2+-activated K+ channels
“Leak” K+ channels
P loop
P loop
Inward rectifier
K+ channels
P loop
P loop
Outside
1
2
3
4
5
6
1
2
3
4
1
2
Inside
N
N
N
COOH
COOH
B
K2P subunits:
15 subfamilies (K2P1–K2P18)
with 15 subfamily members
TMD1
Kir subunits:
7 subfamilies (Kir1–Kir7)
with 15 subfamily members
TMD1
TMD2
Outside
Outside
1
2
3
4
5
6
1
2
3
4
5
6
2
1
3
4
5
6
N
Inside
Inside
NBF1
N
NBF
Walker A
Walker B
COOH
Walker A
Walker B
ABCG1, ABCG4,
ABCG5, ABCG8
Walker B
NBF2
Walker A
ABCA1, ABCB4,
ABCC7 (CFTR)
N
TMD0
TMD1
TMD2
Outside
1
2
3
4
5
1
2
3
4
5
6
1
2
3
4
5
6
Inside
NBF1
Walker B
ABCC8 (SUR1),
ABCC9 (SUR2)
Walker A
Walker B
NBF2
Walker A
182
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COOH
COOH
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Kv subunits:
12 subfamilies (Kv1–Kv12)
with 42 subfamily members
and
KCa subunits:
5 subfamilies (KCa1–KCa5)
with 8 subfamily members
COOH
KATP CHANNELS IN CARDIOPROTECTION
2. Kir6.x subunits
A very large number of studies, performed with diverse
approaches, have established that the Kir6 subfamily members (Kir6.1 and Kir6.2) are the pore-forming components
of the KATP channel (TABLES 1 AND 2). The first member of
the Kir6 subfamily (Kir6.1; initially named uKATP-1) was
identified with homology cloning procedures by screening a
rat pancreatic cDNA library with a GIRK1 (Kir3.1) probe
(374). Kir6.1 was described to have a ubiquitous tissue
expression distribution. The low amino acid identity between Kir6.1 and previously identified Kir subfamily members was responsible for placing this subunit into a new
subfamily, Kir6. The second member of the Kir6 subfamily
(Kir6.2; initially named BIR or ␤-cell inward rectifier) was
subsequently identified by homology cloning, using Kir6.1
as a probe, from a human genomic library (372). Kir6.2
mRNA expression was found in pancreatic ␤-cell, heart,
skeletal muscle, and brain (372). Topology analysis predicts
each of the Kir6.x subfamily members to have two transmembrane regions with intracellular NH2 and COOH termini (FIGURE 4). There is a 71% amino acid identity (85%
similarity) between human Kir6.1 (Genbank accession
number NP_004973) and human Kir6.2 (NP_000516).
The amino acid differences occur mostly in the NH2 and
COOH termini and in an extracellular region (between M1
and M2), where Kir6.1 has a 9-amino acid insert in this region
(FIGURE 6). Kir6.1 and Kir6.2 are well-conserved across mammalian species. Although a third subfamily member has been
identified in Zebrafish (917), the Kir6 subfamily appears to be
restricted to two members in mammals.
C. Regulatory Subunits: The Sulfonylurea
Receptors
Kir6 subunits are unique among the K⫹ channel subunits
since the presence of an auxiliary sulfonylurea receptor
(SUR) subunit is an absolute requirement to form a functional channel. SUR1 was first identified by photolabeling
with glibenclamide (an antidiabetic sulfonylurea), by degenerate PCR, and by screening rat insulinoma (RINm5F)
and hamster insulin-secreting tumor cell (HIT T15) cDNA
libraries (4). Northern blot analysis showed high SUR1
mRNA expression in pancreas, brain, and heart. SUR2A
(one of the major splice variants of the ABCC9 gene) was
identified by homology screening of rat brain and heart
cDNA libraries using SUR1 as a probe (371). A second
major splice variant (SUR2B) was identified by differential
display PCR and RACE amplification of mouse heart
cDNA libraries (117). SUR2A mRNA levels were reported
to be high in heart, skeletal muscle, and ovary and at moderate levels in brain, tongue, and pancreatic islets (although
not expressed in insulin-secreting cell lines), whereas
SUR2B was expressed ubiquitously (117, 371). It should be
noted that other splice variants exist for both SUR1 and
SUR2 (114, 315, 727), but these have not been examined in
detail and the published literature focuses largely on fulllength SUR1, SUR2A, and SUR2B.
FIGURE 3. Subunits of K⫹ channels and of the ATP-binding cassette transporters. A: functionally, K⫹ channels can be grouped in those that
are voltage-gated or activated by cytosolic Ca2⫹. There are also “leak” K⫹ channels and inward rectifier K⫹ channels. A fortuitous relationship
exists between this functional classification and the membrane topologies of the molecular subunits of the channel proteins. Voltage- or
Ca2⫹-activated K⫹ channels consist of subunits with 6 transmembrane (TM) segments and can comprise subunits of the voltage-gated Kv
subfamilies, the KCNQ subfamily, the EAG subfamily (which includes herg), the Ca2⫹-activated Slo subfamily (which actually has 7 TMs), and the
Ca2⫹-activated SK subfamily. The “leak” K⫹ channels consist of 4 TM subunits with 2 pore domains. The inward rectifying K⫹ channels consist
of tetramers of a family of 2 TM subunits, which consists of 7 subfamilies (Kir1 to Kir7), each consisting of several subfamily members (e.g.,
the Kir6 subfamily has 2 subfamily members; Kir6.1 and Kir6.2). B: the ATP-binding cassette transporter family consists of 7 subfamilies (ABCA
to ABCG) with 48 subfamily members (169). The membrane topology of the “half transporters” (such as the ABCG family) has an NH2-terminal
nucleotide binding fold (NBF), 6 TMs, and an intracellular COOH terminus. “Full transporters” (such as ABCC7 or CFTR) appear as a tandem
repeat of the 6 TM domains, with 2 NBFs. The SUR1 and SUR2 subunits are constructed similar to the “full transporters,” but with an additional
5 TM and an extracellular NH2 terminus.
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weakly blocked by glibenclamide (930). The activity of
ROMK1 channels is inhibited ⬃10 –15% by 200 ␮M glibenclamide (456), but the glibenclamide sensitivity is increased (IC50 ⫽ 0.6 ␮M) when ROMK2 is coexpressed in
Xenopus oocytes with a Cl⫺ channel, the cystic fibrosis
transmembrane regulator (CFTR) (553). Although suggested previously (184, 790), SUR2B appears not to interact
with Kir1.1b and is not required to confer the intrinsic low
glibenclamide sensitivity to the channel (456). A recent
study suggested that ROMK2 may contribute to the molecular composition of mitochondrial KATP channels. Specifically, ROMK2 contains an NH2-terminal mitochondrial
targeting signal. Moreover, when heterologously expressed
in H9C2 cells (a rat embryonic heart-derived cell line), a
ROMK2 construct with a COOH-terminal tag was found
to localize to intracellular compartments positive for mitochondrial markers (240). The same study also demonstrated that diazoxide-induced changes in mitochondrial
matrix volume and thallium flux into mitochondria are abrogated by tertiapin Q, a peptide isolated from bee toxin
that blocks certain types of inwardly rectifying K⫹ channels, including Kir1.x (ROMKx), G protein-activated K⫹
channels (Kir3.x or GIRK1/4) (404, 441), and the Ca2⫹activated large-conductance K⫹ channel (BK or MaxiK)
(423). Although this result is intriguing, the possibility that
ROMK subunits may constitute the pore-forming components of mitochondrial KATP channels remains to be independently confirmed by other laboratories and with genetic
approaches.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Kir6.x
SURx
N
P loop
TMD0
TMD1
TMD2
Outside
1
2
1
2
3
4
5
1
2
3
4
5
6
1
2
3
4
5
6
Inside
N
NBF1
COOH
Walker B
Walker A
Walker B
COOH
NBF2
FIGURE 4. Membrane topology and structural organization of the subunits of the sarcolemmal/plasmalemmal KATP channel. The sarco/plasmalemmal KATP channel consists of Kir6.x and SURx subunits. The Kir6.x
subunit (Kir6.1 or Kir6.2) has two membrane-spanning regions (M1 and M2) with intracellular NH2 and COOH
termini. Two SURx subunits have been described: SUR1 and SUR2. Although several splice variants exist for
each, the most commonly studied are the “full-length” SUR1, SUR2A, and SUR2B subunits. The latter two are
alternative splice variants, differing from each other only in the COOH-terminal 42 amino acids. The SURx
subunit has 17 transmembrane regions, arranged in 3 domains: TMD0, TMD1, and TMD2. A conserved
intracellular nucleotide binding fold (NBF1), with Walker A and Walker B domains, exists between TMD1 and
TMD2. A second intracellular nucleotide binding fold (NBF2) exists in the COOH terminus region of the protein.
It is thought that NBF1 binds (and hydrolyzes) MgATP, whereas MgADP binds primarily to NBF2 to stimulate
channel activity.
SUR proteins belong to superfamily ATP-binding cassette
(ABC) proteins (FIGURE 3B), and they are established as
being subunits of the sarcolemmal/plasmalemmal KATP
channel protein complex (FIGURES 4 AND 5). Most of the
ABC proteins transport various molecules across cell membranes at the expense of ATP hydrolysis. A defining characteristic of these proteins is the presence of intracellular
ATP-binding domain(s), known as nucleotide-binding folds
(NBFs) that contain characteristic Walker A and B motifs,
separated by ⬃90 –120 amino acids (168). There are seven
mammalian ABC gene subfamilies. SURx proteins belong
to the ABCC subfamily, which also contains the CFTR (or
ABCC7). SURx proteins have 17 transmembrane regions,
arranged in three domains: TMD0, TMD1, and TMD2,
respectively, consisting of transmembrane segments 1–5,
6 –11, and 12–17 (FIGURES 3B AND 4). This topology, originally proposed by sequence comparison with multidrug
resistance-associated proteins (825), was confirmed experimentally (134).
As mentioned above, there are two major SUR2 splice variants: SUR2A (371) and SUR2B (382). The two variants
differ from each other in their distal COOH-terminal 42amino acid residues (382) due to alternative exon usage.
This rather small difference gives rise to significant functional diversity. For example, pinacidil activates SUR2A/
Kir6.2 and SUR2B/Kir6.2 KATP channels with similar potency (TABLE 3), whereas nicorandil activates the SUR2B/
Kir6.2 channel more than 100 times more potently than
184
SUR2A/Kir6.2 channels (731). Kir6.2/SUR2B channels are
more efficiently activated by cytosolic MgADP than Kir6.2/
SUR2A channels (546, 660). Moreover, whereas Kir6.2/
SUR2B channels are strongly activated by KATP channel
openers such as diazoxide under basal conditions, there is a
requirement for elevated cytosolic MgADP levels in order
for diazoxide to activate Kir6.2/SUR2A KATP channels
(546, 660, 889). The tissue distributions of SUR2A and
SUR2B are also distinct. SUR2A is expressed at high levels
in cardiac ventricle [but not in the rodent atrium (18)],
skeletal muscle, and ovary and at moderate levels in brain
neurons, tongue, and pancreatic islets (18, 371, 932);
SUR2B is more widely expressed, for example, in vascular
smooth muscle, heart, cardiac specialized conduction system myocytes, vascular endothelium, lung epithelium, hair
follicles, renal proximal tubules, renal tubular epithelial
cells, microglia, astrocytes, and the dentate gyrus (48, 50,
86, 144, 439, 491, 496, 626, 637, 705, 734, 906, 907, 932,
933). The transcriptional mechanisms responsible for the
differential tissue distributions of SUR2A and SUR2B remain to be elucidated.
1. Nucleotide binding domains
SURx proteins have two NBFs; NBF1 is located between
TMD1 and TMD2, whereas NBF2 is COOH terminal to
TMD2 (FIGURE 3B). Walker A and Walker B motifs, associated with nucleotide hydrolysis, are present in each of the
NBFs and are typical nucleotide binding domains. The con-
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Walker A
KATP CHANNELS IN CARDIOPROTECTION
sensus sequence for a Walker A motif is G-X-X-X-X-G-K[TS]. The highly conserved lysine (K) residue forms hydrogen bonds with the oxygen atoms of the ␣- and ␥-phosphates of the bound nucleotide (844). The aspartate residue
in the Walker B motifs (the consensus sequence is [RK]-4XG-4X-L-4⌽-D) coordinates Mg2⫹ binding. Mutagenesis of
the Walker A lysine residues in (e.g., K719 and K1384, respectively, in NBF1 and NBF2 of SUR1) or the Walker B asparate residues (e.g., D854 of SUR1) disrupts certain aspects of
KATP channel function, such as the activation by MgADP
and KATP channel opening compounds (14, 285, 827).
The diversity of KATP channel subtypes in various cells originates in part by specific combinations of the various Kir6.x
and SURx subunits (TABLE 2). For example, ventricular sarcolemmal KATP channels and those in pancreatic ␤-cells
have the same pore-forming subunit (Kir6.2) but differ in
the use of the regulatory subunit (SUR2A in the case of the
cardiac channel and SUR1 in the pancreas). Atrial KATP
channels (at least in the rodent) appear to rely on SUR1
subunits. Smooth muscle KATP channels, in contrast, appear
to be composed of Kir6.1 subunits in combination with
SUR2B subunits, and endothelial KATP channels may be
composed of heteromeric Kir6.1/Kir6.2 pore-forming subunits in combination with regulatory SUR2B subunits. The
subunit combination of mitochondrial KATP channels has
not been resolved, but roles for Kir1.1 and/or SUR2 shortform splice variants have been proposed (FIGURE 5).
E. Interactions of KATP Channel Subunits
With Other Subunits and Proteins
A common biological theme is that the biological functions
of proteins, including those of ion channels and transporters, are regulated by other subunits of the protein complex.
The associated subunits may be responsible for regulating
channel function and intracellular trafficking, such as the
Kv␤ subunit that promotes inactivation and surface expression of Kv channels (126), or the early formation of a
Kir6.x/SURx complex, which overcomes the ability of ERresident proteins to prevent surface expression (see sect. V
for more details).
1. Metabolic enzymes
It has long been recognized that cardiac KATP channels are
preferentially regulated by glycolytically derived ATP. With
experiments performed in the open-cell and inside-out
patch-clamp configurations, the Weiss laboratory has demonstrated that cardiac KATP channels are closed equally well
by ATP production from oxidative phosphorylation, the
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D. Subunit Composition Determines the
KATP Channel=s Biophysical and
Pharmacological Properties
creatine kinase shuttle system, and glycolysis (866). However, when intracellular ATP consumption was stimulated,
glycolytic enzymes were far more efficient in blocking KATP
channel activity. This result suggested that the KATP channel
activity is regulated by glycolysis, which alters the nucleotide concentrations in a small submembrane compartment
in the immediate microenvironment of the KATP channel
complex. Preferential regulation of KATP channels by glycolytically derived nucleotides has also been noted in other
tissues, including enterocytes (191) and certain types of
neurons (529, 530, 902). Findings such as these have been
interpreted that key glycolytic enzymes are located near
KATP channels at the plasma(sarco)lemma (866). Indeed,
using two-hybrid and coimmunoprecipitation assays, the
glycolytic enzymes aldolase (ALD), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), triosephosphate isomerase
(TPI), pyruvate kinase (PKM), and lactate dehydrogenase
(LDH) were found to be de facto interacting proteins of the
cardiac KATP channel (139, 179, 357, 409). At least one of
these enzymes (aldolase) appears to interact with an intracellular coiled-coil domain within the NBF1, close to the
12th transmembrane domain of SUR2 (357). Using unbiased proteomic approaches in a search for KATP channel
interacting proteins, we recently performed mass spectrometry of immunoprecipitates of KATP channel complexes
(357, 433). Pathway analysis of the identified interacting
proteins revealed glycolysis to be the most significantly represented pathway (357, 433). Patch-clamp experiments
showed that the catalytic activity of glycolytic enzymes can
regulate KATP channel activity, even when experiments are
performed in with inside-out membrane patches (179). The
distal, ATP-producing glycolytic enzymes, such as PKM
were particularly effective in regulating KATP channel activity (357). Experimentally, KATP channels readily open when
inhibiting mitochondrial ATP production (e.g., with cyanide or DNP) and the physiological relevance of glycolytic
regulation of KATP channels is not immediately obvious.
Although it remains an untested idea, it is possible that local
ATP depletion from glycolytic sources is responsible for
cardiac KATP channel opening and action potential duration
adaptation that occurs with a sudden increase in the heart
rate (941). This mode of regulation may become more pronounced with aging, since glycolytic inhibition in aged rat
hearts causes action potential shortening and arrhythmias
that can be prevented by KATP channel block with glibenclamide (575). Competition for local glycolytically derived
ATP may also be responsible for the known functional interaction between the KATP channel and the Na⫹/K⫹ pump,
which has been observed in several tissues, including frog
skin (829), neurons (8), the kidney (548), skeletal muscle
(663), smooth muscle (269), and the heart (411, 646). Although the physiological relevance of this functional interaction is obvious, it has been suggested to be important in
the protective effects of ischemic preconditioning (IPC)
(331).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
A
Kir6.x
SURx
SUR2 variant
Kir1.1
FIGURE 5. Schematic diagram of KATP channel subunits. A: the sarcolemmal/plasmalemmal KATP channels
are hetero-octameric complexes. The channel consists of four members of the Kir6 subfamily members
(Kir6.1 and/or Kir6.2) and four members of the sulfonylurea receptor family (SUR1 and/or SUR2; or splice
variants of these subunits). ATP blocks the channel by direct binding to Kir6.x intracellular domains, whereas
Mg2⫹ complexes of nucleotides regulate the channel activity by binding to intracellular nucleotide binding folds
(NBF1 and NBF2) of the SURx subunits. B: schematic representation of proposed subunits of the mitochondrial KATP channel. The pore-forming part of the channel may be composed of Kir1.1 (ROMK) subunits, which
in heterologous expression systems are activated by MgATP when expressed alone. ATP inhibition of the
channel complex is therefore likely to be conferred by additional subunits. It is possible that unique short-form
SUR2 splice variants may be a regulatory subunit of the mitochondrial KATP channel, but additional forms of
regulation must be present since the short-form SUR2 splice variant is not blocked by sulfonylureas. The nature
of any additional subunits, the molecular composition of the channel, and stoichiometry of assembly are
currently unknown.
Aside from glycolytic enzymes, KATP channels also interact
with (and are regulated by) enzymes of intracellular phosphotransfer networks (197), which transfer phosphoryls
between different intracellular compartments without causing significant alterations in the cytosolic levels of adenine
nucleotides (914). These phospho-relays provide energy
transfer pathways between flux-generating (ATPases) and
flux-responding (glycolysis and oxidative phosphorylation)
processes. Adenylate kinase (AK), for example, catalyzes
the reversible phosphotransfer between ADP and ATP in
the presence of AMP and Mg2⫹ as follows:
Adenylate Kinase
ATP ⫹ AMP→ ADP ⫹ ADP ⫹ Mg2⫹
It has been suggested that AMP, which is produced by
other biochemical pathways, is delivered to the mem-
186
brane by the AK-catalyzed phosphotransfer system. In
the microenvironment of the channel complex, AK then
converts the AMP to ADP (and in the process consumes
ATP). The resulting change in the ATP/ADP ratio in the
microenvironment of the channel is sufficient to lead to
KATP channel opening (100, 208). In contrast, creatine
kinase (CK), which also interacts with KATP channel subunits (141), mediates this reversible phosphotransfer reaction:
Creatine Kinase
ADP ⫹ creatine phosphate↔ ATP
⫹ creatine
It has been suggested that this reaction of CK promotes
localized removal of ADP and delivery of ATP to KATP
channel and thereby to block the KATP channel (13, 197).
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B
KATP CHANNELS IN CARDIOPROTECTION
2. Other interacting proteins
IV. MOLECULAR MECHANISMS THAT
REGULATE KATP CHANNEL FUNCTION
A. Kir6 Subunits Interact With SUR
Subunits: Stoichiometry of Interaction
A novel radioiodinated azidoglibenclamide analog was
found to photolabel a ⬃175 kDa protein in microsomes
isolated from porcine cerebral cortex (709). Interestingly,
the same group later found that by omitting the “boiling
step” prior to SDS-PAGE, a novel colabeled 38 kDa protein
was revealed (710). The Bryan laboratory demonstrated the
38 kDa protein to be Kir6.2, which provided the first bio-
The stoichiometry of Kir6.2 and SUR1 interactions has
been further investigated with coexpression approaches.
The Seino group found that currents could be recorded
from COS1 cells transfected with a concatemeric construct
consisting of a tandem Kir6.2-SUR1 subunit (373), suggestive of a 1:1 stoichiometry of assembly. The Bryan group
used a similar approach and reached the same conclusion
(122). Shyng and Nichols (737) extended this approach by
generating a mutant Kir6.2-N160D subunit, which confers
strong rectification properties to the normally weakly rectifying channel (see sect. IIE). By coexpressing different ratios of wild-type or Kir6.2-N160D mutant subunits, or dimeric (SUR1-Kir6.2) constructs, they were able to determine that the KATP channel pore is lined by four Kir6.2
subunits and that each Kir6.2 subunit requires one SUR1
subunit to generate a functional channel, a model that is
consistent with an octameric or tetradimeric (Kir6.2-SUR1)
structure. One assumes that the Kir6.2-SUR2x complex
also has this octameric structural organization.
B. The Channel Pore
The pore of a K⫹ channel is comprised of a conserved poreforming domain (or the “P loop”) between TM1 and TM2,
which is a short amino acid segment that dips into the
membrane (188). The P domain of K⫹ channel principal
subunits is critically important for channel function and ion
permeation. Mutagenesis and three-dimensional structural
studies have demonstrated that this domain forms the K⫹selective pore of the channel (188, 341, 775). The primary
sequence of the P loop of Kv subunits has the signature
sequence T-V-G-Y-G (standard single letter amino acid
codes) (126). For the Kir subunits, the P-loop “signature
sequence” is represented by T-I-G-[YF]-G (FIGURE 6).
C. Block of the KATP Channel by Intracellular
ATP
The normal requirement is for Kir6.x and SURx subunits to
assemble before surface expression occurs. However, ex-
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Proteomic analysis has identified several types of proteins as
potential KATP channel interacting partners in the cardiovascular system (the heart and endothelial cells) (357, 433).
The veracity of the majority of these proteins awaits independent confirmation. It is likely that this list includes many
false positives and several proteins that may only interact
weakly or transiently. The proteins identified with quantitative mass spectrometry at high confidence (i.e., they were
immunoprecipitated by at least two separate antibodies and
significantly enriched relative to negative control reactions)
included proteins involved in metabolic pathways, cytoskeletal organization (actin, myosins and microtubules),
and subcellular protein localization/trafficking. In addition
to this list of candidates, there is evidence that syntaxin 1A
may interact with SURx subunits and that this interaction
regulates the function of KATP channels in pancreatic ␤-cells
and in cardiac myocytes (104, 108, 421, 422, 634) and that
this binding may depend on PIP2 levels (883). In cardiac
muscle, ankyrin-B was found to interact directly with the
Kir6.2 subunit and to regulate the membrane expression
and function of KATP channels in the heart (494). The interaction with ankyrin-B is likely to reflect a trafficking or
membrane anchoring function, and it is possible that ␤IVspectrin may have a similar role, as has been described for
the pancreatic KATP channel (449). In vascular smooth muscle, caveolin-1 was described to interact with the KATP
channel and that this suppresses gating by reducing the
sensitivity of channels to the stimulatory influence of
MgADP (162). Kir6.2 was also described to associate with
caveolin-3 (but not caveolin-1), and it was found that ventricular KATP channels are negatively regulated by caveolin
(256). A possible role for this interaction and the presence
of KATP channels in caveolae is to localize receptor signaling
to KATP channels in smooth muscle and the endothelium
(606, 687, 688). A full understanding of subunits of the
KATP channel megadalton protein complex, and how they
regulate the function and trafficking of KATP channels in the
cardiovascular system, is still in its infancy and much can be
learned from further exploring this topic.
chemical evidence for direct physical interaction between
Kir6.2 and SUR1 (122). In the latter study, heterologously expressed Kir6.2 and SUR1 subunits (in Cosm6
cells) were both labeled by 125I-azidoglibenclamide,
whereas other Kir subunits (Kir1.1 or Kir3.4) were unlabeled. Moreover, Kir6.2 and an NH2-terminal Histagged SUR1 could be copurified from digitonin-solubilized membranes of COSm6 cells expressing both subunits, with an estimated molecular mass of the protein
complex to be ⬃950 Da (122), consistent with at least an
octameric composition of four Kir6.2 and four SUR1 subunits. Coimmunoprecipitation assays with anti-Kir6.2 antibodies also demonstrated a specific interaction between
Kir6.2 and SUR1 in membranes isolated from COS cells
co-expressing the two subunits (522) and between the in
vitro translated Kir6.2 and SUR2A proteins (522).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
perimentally it is possible for channels to be formed by
Kir6.2 subunits in the absence of SURx. The Kir6.2 COOH
terminus contains an ER retention signal (see sect. VB).
Mutagenesis of this signal sequence, or deleting it with a
COOH-terminal truncation (e.g., Kir6.2⌬C26), allows
SURx-independent Kir6.2 surface expression. These
Kir6.2⌬C26 channels can still be blocked by ATP (821),
demonstrating that the Kir6.2 subunit has an intrinsic ATP
inhibitory site. However, no classical consensus motif for
ATP binding is evident in the amino acid sequence of
Kir6.2. Neutralization of a specific lysine residue
Kir6.2⌬C26-K185Q was found to substantially decrease
ATP sensitivity (821), suggesting that this lysine might be
involved in ATP-binding. Systematic mutagenesis of “intracellular” charged residues identified several amino acids
that alter ATP sensitivity (e.g., R50, C166, I167, T171,
K185) (820). Some of these mutations lowered the intrinsic
open probability of the channel. The apparent change in
ATP sensitivity might have been due to the fact that ATP
binding is favored during the long closed state of the channel (12, 739). Mutagenesis of R50 and K185 markedly
altered ATP sensitivity without altering kinetics and were
therefore assumed to be involved in ATP binding (820).
R201 has been identified as another residue critical for ATP
binding in subsequent mutagenesis studies (667, 738). It is
believed that channel inhibition by ATP may involve interaction of ATP=s ␣-phosphate with R201, the ␤-phosphate
with K185, and the ␥-phosphate with R50 from an adjacent
subunit (405, 667) (FIGURE 7). A more complete structural
model of the ATP-binding site of the Kir6.2 subunit has
been published (16). The KATP channel is powerfully activated by phosphatidylinositol 4,5-bisphosphate (PIP2) in
the membrane (see below). The Kir6.2 residues R54, R176,
R177, and R206 are thought to bind PIP2 (52, 738, 740).
The PIP2 binding site overlaps with that of ATP, and it is
believed that ATP binding to Kir6.2 destabilizes the channel=s interaction with PIP2, thereby contributing to a transition to a closed state (405, 596, 740).
188
D. Simulation of KATP Channel Opening by
Intracellular MgADP
ATP blocks the KATP channel by binding to the Kir6.2 subunit
(see below). However, coexpression of Kir6.2 with SURx
strongly alters the channel=s ATP sensitivity. For example, ATP
inhibits heterologously expressed Kir6.2/SUR1 currents with a
half-maximal inhibitory concentration (IC50) of ⬃10–20 ␮M
(596), whereas channels consisting of Kir6.2 alone (e.g.,
Kir6.2⌬26) have a 10-fold reduced ATP sensitivity (IC50 ⬃140
␮M) (37, 821). Binding of nucleotides (and Mg2⫹) to either
NBF1 or NBF2 could therefore potentially participate in ATP
inhibition. However, mutagenesis within NBF1, NBF2, or the
linker region between the NBFs, does not prevent ATP inhibition
(285, 739). It is likely, therefore, that the altered ATP sensitivity of
coassembled Kir6.2/SURx channels is not due to ATP binding to
the NBFs. Recent studies suggest that interaction domains between Kir6.2/SURx, mediated by cytoplasmic domain interfaces
near the membrane, may regulate ATP sensitivity (644). However, the molecular underpinnings by which Kir6x/SURx assembly affects ATP sensitivity remain elusive.
Nucleotides do indeed bind to SURx=s NBF1 and NBF2,
and the reader is referred to excellent reviews on SUR proteins and their nucleotide binding properties (5, 25, 92,
543, 719). Support for the notion that MgADP stimulates
the KATP channel by interacting with SURx comes from the
finding that Kir6.2 expressed in the absence of SURx (e.g.,
Kir6.2⌬36) is not activated by MgADP (287). Both MgATP
and MgADP have been reported to activate KATP channels
by acting on the NBFs. For example, mutagenesis of the
conserved Walker A lysine residues in (e.g., K719 and K1384
in SUR1) or the Walker B asparate residues (e.g., D854 of
SUR1) inhibits activation of the KATP channel by MgADP
(14, 285, 827). Direct evidence for nucleotide binding to
NBFs come from photoaffinity labeling with 8-azido[32P]ATP (827). Mutagenesis experiments revealed that
SUR1 NBF1 has high affinity for ATP binding (Mg2⫹ is not
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FIGURE 6. The pore domain of inward rectifier K⫹ channel subunits. The multiple sequence alignment of the
region between TM1 and TM2 (note that the TMs are not shown in full and the NH2 and COOH termini are not
included) of mammalian Kir subunits demonstrates strong sequence conservation, depicted by the shading.
Strong sequence conservation in the region between TM1 and TM2 is represented by C-3x-⌿-5x-A-F-[LS]-F-x⌿-E-x-[QE]-x-T-I-G-[YF]-G, with ⌿ representing the aliphatic amino acids V, I, or L (1).
KATP CHANNELS IN CARDIOPROTECTION
outside
K39
R50
inside
I182
FIGURE 7. Structural model of the Kir6.2 subunit. A structural model of the Kir6.2 subunit, based on Antcliff
et al. (16). The four chains of the tetrameric Kir6.2 protein are shown in separate colors, and the membrane
is represented by a shaded box. The surface-filled ATP molecule is colored by atom property. The right panel
shows an expanded view of the ATP binding pocket (one of the Kir6.2 chains is hidden for clarity), and some
of the residues involved in ATP binding are illustrated. The model coordinates were kindly provided by Dr.
Frances Ashcroft (Univ. of Oxford, UK).
required for ATP binding). Moreover, they showed that
MgADP binding to NBF2 antagonized ATP binding to
NBF1. These findings were verified when the NBF1 and
NBF2 domains were expressed individually. NBF1 was affinity labeled by 8-azido-[32P]ATP with the radioactive
phosphate group present in either the ␣ or ␥ position,
whereas NBF2 was labeled only by 8-azido-[␣-32P]ATP
(544, 545). Direct evidence for ATP hydrolysis was presented with the finding that immunoprecipitates obtained
with anti-KATP channel subunit antibodies contain ATPase
activity (66). Moreover, the ATPase activity of purified
SUR2 NBF2 was significantly higher than that of NBF1 (66,
939). Support for the idea that ATP hydrolysis is required
for KATP channel activation comes from experiments using
nucleotide trapping procedures (vanadate or beryllium-fluoride) to stabilize the ATPase cycle in distinct conformations (939). It has also been demonstrated that diseasecausing mutations in SUR1 NBF2 (R1380L and R1380C,
which are linked to neonatal diabetes) activates the KATP
channel by increasing the channel complex=s ATPase activity (167). Collectively, these data suggest that ATP bound to
NBF2 is hydrolyzed to MgADP and that NBF1 has little
ATPase activity. Although elegant, the experiments with
isolated NBF proteins should be interpreted with some caution since in general NBF dimerization is favored upon nu-
cleotide binding and ATP hydrolysis occurs with cooperative interaction of the dimerized NBFs. Indeed, the ATPase
activity of SUR1 is substantially less than that of the isolated NBF2 (166). Furthermore, not all data are consistent
with the idea that ATP hydrolysis is required for basal KATP
channel function. For example, mutagenesis of the conserved Walker A lysine and/or Walker B aspartate residues
(see sect. IIIC1), which as expected disrupts ATPase activity
in other ABC proteins (777, 795), does not substantially
affect basal KATP channel function or ATP inhibition (66,
151, 285). It may be possible for the hydrolyzed MgADP to
be trapped in NBF2, which may be responsible for channel
activation. This view is not entirely consistent with the
strong activation of KATP channels by MgADP in excised
patches (at a constant MgATP concentration). An alternate
view is that ATP hydrolysis at NBF2 is epiphenomenon and
that MgADP binding directly activates the channel (596).
Further research is needed to resolve these issues.
E. Mechanisms of Rectification
As mentioned in section II, the current-voltage relationship
of KATP channels exhibit weak inward rectification properties (reduced outward current at voltages positive of the K⫹
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MONIQUE N. FOSTER AND WILLIAM A. COETZEE
F. Regulation of the KATP Channel by PIP2
Phospholipids, such as the membrane PIP2, activates the
KATP channel (52, 214, 349, 740) and increases the channel=s intrinsic open probability (Po) by prolonging the mean
open time and shortening the mean closed time (214). The
sensitivity of the KATP channel to ATP inhibition is much
reduced by PIP2 (52, 214, 740). A part of this effect is
indirect (210, 814) since ATP stabilizes the closed state of
the channel (736, 814), which is less accessible when the Po
is high. The high Po may also be responsible for the effect of
PIP2 to mitigate activation of KATP channels by MgADP, to
reduce channel inhibition by sulphonylureas (463), and to
attenuate rundown (214). However, the ATP sensitivity of a
COOH-terminal truncated Kir6.2 channel is also reduced
by PIP2, and this occurs in the absence of significant effects
on Po (215), which suggests that PIP2 additionally have
direct effects on ATP binding. Indeed, competition occurs
between ATP and PIP2 binding for biochemically purified
Kir6.2 protein (857) or of the Kir6.2-containing channel
(532). Molecular modeling and mutagenesis studies suggested that the ATP and PIP2 binding sites within the Kir6.2
subunit overlap (145, 307). Thus binding of PIP2 in the
membrane to the Kir6.2 subunit seems to have important
functional consequences on KATP channel function. An
open question remains whether this mode of channel regulation occurs physiologically. Using a GFP-tagged PLC␥
190
PH-domain construct to visualize intracellular PIP2, a case
has been made that ␣1-adrenoceptor stimulation inhibits
ventricular myocyte KATP channels by reducing the membrane PIP2 levels (332). There are not many other examples
of studies showing that PIP2 regulation of KATP channels
occur under physiological, pharmacological, or pathophysiological conditions. PIP2 may also have a function during
biosynthesis and vesicle trafficking of ion transporters and
channels: low levels of PIP2 in the intracellular membranes
may keep channels inoperative until they reach the surface
membranes to be activated by higher local PIP2 levels (350).
V. SYNTHESIS, TRAFFICKING, AND
DEGRADATION OF KATP CHANNEL
PROTEINS
It is easy to visualize KATP channels as being uniformly expressed on the surface of cardiac myocytes at a constant density. However, the surface expression of KATP channels may be
quite labile and regulated by a fine balance between de novo
synthesis, assembly, anterograde trafficking, subunit interaction, posttranslational modifications such as glycosylation,
membrane anchoring, and endocytic recycling (FIGURE 8).
Please refer to an excellent recent review that summarizes the
literature and our current understanding of the dynamic regulation of ion channels in cardiomyocytes (45). The text below
specifically deals with KATP channels, which are not highlighted in the review mentioned. Much of the text that follows
is based on data obtained in heterologous expression systems
or in cell types other than cardiomyocytes. Given the evolutionary conservation of trafficking mechanisms from yeast to
mammals, this information is likely directly relevant to the
cardiomyocyte, smooth muscle cell, or endothelial cells.
A. Regulation of KATP Channel Subunit
Expression
The origin of any protein is the nucleus, and the transcriptional regulation of gene expression constitutes an important control point. Transcriptional regulation of the KATP
channel subunit genes (KCNJ8, KCNJ11, ABCC8, and
ABCC9) has not been studied systematically. A recent study
showed that the ABCC8 and ABCC9 promoters can be
methylated in HL-1 cells and that methylation decreases
mRNA expression (220). Although these genes were not
methylated in the mouse heart, the possibility is raised that
DNA methylation may regulate transcriptional activity of
KATP channel genes.
The transcription of KATP channel subunit mRNA can be regulated during pathophysiological situations such as ischemia/
reperfusion. In a model of left coronary occlusion rat hearts,
ion channel remodeling was demonstrated to occur with the
development of postischemic dilated cardiomyopathy (381).
Specifically, Kir6.1, SUR1, and SUR2A mRNAs were upregu-
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equilibrium potential). Physiologically, inward rectification
of K⫹ channels is an important energy-saving mechanism:
the K⫹ efflux resulting from open K⫹ channels during the
long cardiac action potential must be restored by the
Na⫹/K⫹ pump at the expense of ATP hydrolysis. A low
overall membrane conductance during the long action potentials and limiting outward K⫹ flux by inward rectification mechanisms is therefore energetically beneficial. Early
studies have noted a negative slope region of the KATP channel unitary current-voltage relationship (607, 815), indicative of inward rectification. It was found that “intracellular” Na⫹, TEA⫹, and Tris can cause inward rectification;
intracellular pore block (to reduce outward current) was
proposed as the mechanism (135, 416). Intracellular Mg2⫹,
at concentrations in the low millimolar range, was subsequently demonstrated unidirectionally to block outward
KATP channel current (359). It is now recognized that physiological levels of intracellular Na⫹ and Mg2⫹ contribute to
KATP channel inward rectification. Naturally occurring intracellular polyamines (e.g., spermine, spermidine, and putrescine) are also major determinants of KATP channel current rectification (225, 521, 597). These long and thin polyvalent cations enter the KATP channel subunit inner
vestibule and interact with residues of the Kir6.2 subunit to
block outward K⫹ flux (524, 736). As demonstrated by a
Kir3.1 crystal structure (603), it is likely that polyamines
bind within an extended cytoplasmic pore that is formed by
the Kir6.2 intracellular NH2 and COOH termini (470).
KATP CHANNELS IN CARDIOPROTECTION
Anchoring: lipid rafts
Barbed
Daughter
filament
Mother
filament
Fusion:
Syntaxins, etc.
Anchoring: SPD95,
CASK, SAP97,
Ankyrin
EHD2
ARP2/3
complex
Glut4
β2 receptor
Transferrin
Pointed
Rab10
Dennd4C
EHD1
EEA1
Rab5
Rab11
EHD1
EEA1
Rab5
Rab4
Rab17
Glycolyslation
ERC
Rab4
EHD3
Early endosome
M6PR
CTxB
Golgi
COPI
Rab2
COPII
Rab1
M6PR
Rab7a
EHD4
Rab9
Hsp70, Hsp90,
calnexin, β-subunits
ER
EGFR
Nucleus
Forward trafficking
motifs (unknown)
Lysosome
ER retention
motifs (RXR)
LAMP2
Late endosome
Rab7b
LAMP2
FIGURE 8. Processes responsible for the synthesis, trafficking, and degradation of membrane proteins. A
simplified schematic representation of the anterograde (forward) vesicular trafficking pathway by which newly
synthesized ion channels reach (and are retained at) the surface membrane, as well as established endocytic recycling
pathways. Also shown are some of the major trafficking proteins involved and examples of pathway-specific cargo (red
boxes). For detailed information, the reader is referred to specialized reviews on this subject (76, 87, 549, 749, 761).
lated 8 –20 wk postinfarction. A strong increase in Kir6.1
mRNA expression was observed after renal ischemia or regional myocardial ischemia in the rat (9, 724), without significant changes of Kir6.2 and SUR2 mRNA expression levels.
The local renin-angiotensin system and tumor necrosis factor
(TNF)-␣ may play a role in the upregulation of Kir6.1 after
ischemia (10). Kir6.1, Kir6.2, SUR1, SUR2A, SUR2B mRNA
expression is strongly upregulated in the border zone of the rat
heart at 7–140 days after coronary artery ligation, and their
increased expression levels correlate with that of forkhead
transcription factors FoxF2, FoxO1, and FoxO3 (638). Gelshift assays demonstrated that FoxO1 binds to Kir6.1 in
mouse atrial HL-1 myocytes (638).
During chronic hypoxia, upregulation of Kir6.1 protein
levels occurs in rat heart and brain, whereas Kir6.2 is
downregulated (253). Hypoxia was also reported to upregulate Kir6.1 (560) and SUR2A (140) mRNA in H9c2
rat heart cells. The upregulation of SUR2A mRNA ex-
pression by chronic hypoxia was described to occur independently of HIF-1␣ activity, independent in the H9c2
cells (140). Kir6.1 is also upregulated in the atria of
children with congenital heart disease, possibly due to
venous hypoxemia; this effect appears to be mediated by
hypoxia-induced activation of HIF-1␣ and FOXO1
(652). In patients with mitral valve disease, cardiac
Kir6.2 mRNA expression positively correlates with venous oxygen content and with HIF-1␣ mRNA expression, further supporting a role for hypoxia-sensitive transcription factors to regulate KATP channel expression.
The significance of strong hypoxia-induced upregulation
of Kir6.1 in the heart is not obvious at present, since this
subunit is generally not assigned a function in cardiomyocytes. Further studies are needed to determine if Kir6.1
has a novel functional role in posthypoxic ventricular
myocytes or whether Kir6.1 is upregulated in other cell
types (e.g., in the endothelium or coronary arteries, perhaps as a result of increased vascularization).
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Rab11
EHD1
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
B. Protein Assembly and Quality Control
Mechanisms in the ER
Not all proteins are folded properly, despite the existence
of a multitude of control mechanisms. If misfolded proteins accumulate, an ER stress response may ensue (855).
The misfolded proteins are normally retained within the
ER and are disposed of by the ERAD system (673). Upon
recognition, a misfolded protein is transported from the
ER to the cytoplasm (also known as retrotranslocation),
where it is ubiquitinated by E3 ligase and released in the
cytoplasm for degradation in a nonlysosomal manner by
the proteasome. There is evidence that KATP channels can
be degraded by the ERAD pathway. First, SUR1 and
Kir6.2 have been demonstrated to form a complex with
Derlin-1 and an associated p97 protein (858). Derlin-1
participates in the recognition of misfolded proteins, and
it forms the retro-translocation channel, whereas p97 is
an ATPase that links the misfolded proteins to ubiquitin
ligases (656). Second, KATP channel subunits can be ubiquitinated (788). Third, KATP channel subunit degradation can be prevented by MG132, which is an inhibitor of
the proteasome (788, 891). It should be noted that these
studies were performed with the Kir6.2/SUR1 channel
(pancreatic ␤-cell form). It remains to be demonstrated
that KATP channels in the cardiovascular system participates in ERAD.
Correctly folded proteins are assembled within the ER before exiting and being transported to the surface. Following
the molecular cloning of KATP channel subunits, an early
observation was that Kir6.x and SURx subunits need to be
coexpressed to generate functional channels (371, 374). A
key finding in understanding this phenomenon came from a
study in which a Kir6.2 subunit with a truncated COOH
terminus (by 26 –36 amino acids) was found to express
functional channels in the absence of SURx subunits (821).
We now know that trafficking of unassembled Kir6.x or
SURx subunits to the plasma membrane is prevented by an
arginine-based ER-retention/retrieval signal, composed of
192
Do KATP channel subunits have anterograde trafficking signals? Certain inward rectifier K⫹ channel subunits, such as
Kir2.1, efficiently traffic to the surface membrane. In a
study with subunit truncation and chimeras with other proteins, the presence of an ER export signal (FCYENE) has
been identified in the Kir2.1 COOH terminus (531). The
KATP channel pore-forming Kir6.x subunits lack a corresponding motif. An anterograde trafficking signal that is
required for the assembled KATP channels to exit the ER/cisGolgi compartment was described for the SUR1 subunit
(725). Truncation experiments suggested that the last 5–13
amino acids of the SUR1 COOH terminus are required for
surface expression. At present, this study is unconfirmed,
given that other groups found that SUR1 COOH-terminal
truncations did not markedly inhibit surface expression
(268, 685, 712). Thus it is therefore questionable whether
KATP channel subunits contain any specific anterograde
trafficking signals. It is known, however, that binding of the
channel complex to 14-3-3 proteins promotes the cell surface transport of correctly assembled complexes and that
this interaction is without effect on the KATP channel function (346).
C. Anterograde Trafficking of the Assembled
KATP Channel Protein Complex
After exiting the ER, KATP channel proteins presumably
follow the regular anterograde trafficking pathway through
the Golgi apparatus to the cell surface (FIGURE 8). Protein
glycosylation occurs in the ER and Golgi compartments
(666). SUR1, for example, is modified by this form of posttranslational modification at two N-linked glycosylation
sites (651). This mature, complex glycosylated form of
SUR1 resolves with lower electrophoretic mobility when
studied with SDS-PAGE and can be distinguished from the
core-glycosylated form (916). The N-glycosylation that occurs in the ER is sensitive to Endo H digestion, whereas
proteins glycosylated in the Golgi resist the Endo H treat-
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Membrane proteins, such as ion channel subunits, are
translated in the rough ER and then enter the endoplasmic reticulum in an unfolded state through the translocon, which is a protein-conducting channel (656). Within
the ER, many proteins coordinate to ensure the proper
function and assembly of newly synthesized proteins.
Chaperone proteins assist with folding and membrane
integration, whereas other modifying enzymes ensure appropriate posttranslational modifications, such as glycosylation or disulfide bond formation (81). This is also the
time when subunits are assembled into their unique multisubunit complexes. It is only when the channel protein
complex is correctly assembled and modified that it
leaves the ER to be transported through the anterograde
trafficking pathway and the Golgi apparatus, with its
final destination as the surface membrane.
the three amino acids RKR, respectively, in the Kir6.2
COOH terminus and in a cytoplasmic loop of SURx located
between the 11th transmembrane domain and NBF1 (FIGURE 4) (916). It should be noted that the arginine-based
motif is “RKR” in SUR1 and “RKQ” in SUR2. The dibasic
motif RKR may interact with COPI proteins, which results
in ER retention (610, 910). Subunit assembly is thought to
shield these dibasic motifs from ER resident proteins. In
addition to the ER retention signal present in the distal
Kir6.2 COOH terminus, other signals within the M2 transmembrane and the proximal COOH-terminal regions also
contribute to the inability of Kir6.2 to traffic to the membrane in the absence of SURx (361). The presence of these
motifs therefore most likely ensures that only fully assembled octametric KATP channel complexes are able to continue on trafficking route towards the plasma membrane
(915).
KATP CHANNELS IN CARDIOPROTECTION
ment. Since the mature form of SUR1 is resistant to Endo H
digestion (18, 725), we can conclude that KATP channels
traffic through the Golgi, where they are glycosylated. Although not demonstrated, one can assume that KATP channels follow the canonical forward trafficking pathway
(749). Packed in vesicles, they are transported through the
cis-Golgi and trans-Golgi along microtubules tracks to the
cell surface, driven by specific molecular motors.
D. Membrane Delivery and Anchoring
Scaffolding proteins have long been recognized to localize
ion channels and to anchor them to the membrane in specific areas, such as the postsynaptic density (PSD) of neurons (846). The membrane-associated guanylate kinase
(MAGUK) protein family has a central role in controlling
the localization of proteins in the PSD. Members of the
MAGUK protein family, including SAP97 and PSD-95, are
known regulators of ion channel trafficking and localization (242), but there are no reports indicating that KATP
channels are regulated by these proteins. In contrast, elements of the cytoskeletal network have a recognized role.
Ankyrin functions as a linker between integral membrane
proteins and the actin-spectrin-based cytoskeleton (146,
672). Disruption of any element within this cortical cytoskeletal network has effects on KATP channel function. Disrupting the actin network (e.g., with cytochalasin B) enhances KATP channel activity by reducing its sensitivity to
inhibitory intracellular ATP (802) and decreases channel
block by glibenclamide (82). ␤IV-Spectrin has been shown
to serve as a structural and signaling platform for KATP
channels in the pancreatic islet (449), and one assumes that
this is also the case in the cardiovascular system. Ankyrin-B
(but not ankyrin-G) interacts with Kir6.2 (but not Kir6.1) at
E. Endocytosis
After reaching the surface membrane, KATP channels do not
remain there. In general, cells internalize the equivalent of
their entire surface area up to five times per hour, and most
endocytosed proteins and lipids are recycled back to the
plasma membrane (760). Some membrane proteins can be
reused hundreds of times through specific recycling pathways (282). Endocytic recycling is a rapid process, and it
occurs in the order of minutes (760). For ion channels, this
process is potentially a powerful mechanism to control their
surface density and hence their function. The surface density is determined by a delicate balance between the rates of
endocytosis and exocytosis, which in turn are regulated by
specific specialized trafficking proteins. We are only now
starting to understand the complex events involved in the
endocytic recycling of KATP channel subunits.
Several reports have demonstrated that KATP channels are
endocytosed (89, 363, 537). A dominant-negative dynamin
(K44E mutant) was shown to prevent internalization of
both SUR1 and SUR2-contaning channels (363, 537).
Moreover, KATP channel subunit endocytosis can be inhibited by the dynamin inhibitor dynasore (89) or by a dominant-negative dynamin peptide (741). Dynamin-mediated
endocytosis can occur through a clathrin-mediated pathway or may be clathrin-independent, in which case a role
may exist for caveolae and/or RhoA (550). Published data
are not uniform regarding the endocytosis mechanism(s) of
KATP channel subunits. Several studies suggested that KATP
channel endocytosis occurs as clathrin-coated pits. For example, internalized channels colocalize with clathrin, and a
dominant-negative form of ␮2 subunit of the AP2 adaptor
complex (D176A/W421A), but not the wild-type ␮2, inhibits KATP channel endocytosis (537). Other studies report
that, in smooth muscle, PKC-stimulated KATP channel endocytosis is caveolin-dependent since it was inhibited by
interventions that deplete membrane cholesterol and
siRNA knockdown of caveolin-1 (401). Caveolins may link
KATP channels to caveolae and receptor signaling (see sect.
IIIE), and this finding does not necessarily signify a role in
endocytosis. Moreover, caveolae are relatively immobile
membrane structures that are generally not associated with
endocytosis (804). Overall, therefore, it appears that KATP
channels are constitutively endocytosed through a pathway
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The delivery of new channels to the membrane, as well as
their anchoring at the membrane, is a topic recently covered
in a review (45). The fusion of trafficking vesicles to the
membrane is controlled by the SNARE complex (750). Proteins of the SNARE complex have been described to interact
with ion channel subunits. For example, SNAP-25 has been
described to interact with several types of Ca2⫹ channel
subunits and the K⫹ channels subunit Kv2.1 (335, 541,
875). Another SNARE protein, syntaxin-1A, also interacts
with Ca2⫹ and K⫹ channel subunits and functionally regulates these channels (119, 174, 541, 562, 819). Syntaxin-1A
also interacts with proteins of the ABCCx gene family, including CFTR (ABCC7), SUR1 (ABCC8), and SUR2
(ABCC9) (252, 421, 634). Syntaxin-1A regulates both the
trafficking and gating of CTFR (791). By binding to the
intracellular nucleotide binding folds of SUR1 and SUR2,
syntaxin-1A negatively regulates KATP channels (104, 421,
634). The inhibition is due in part by accelerated endocytosis of surface channels, but it also regulates KATP channel
surface expression by inhibiting the early secretory pathway
(108).
a motif contained within residues 313–325 of the subunit=s
COOH terminus (448). Disrupting ankyrin-B expression
impairs KATP channel KATP channel surface expression, but
also has functional effects that have been reported. For
example, channels comprised of Kir6.2 subunits that lack
the ankyrin-B binding domain have a decreased ATP sensitivity (448, 494). Thus scaffolding and anchoring proteins
can regulate both the surface density and function of KATP
channels, and this mode of regulation can be important in
human disease and cardiomyopathies (148).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
mediated by clathrin and dynamin, but that there may also
be a role for a caveolin-based receptor-stimulated endocytosis (at least in smooth muscle).
F. Endocytic Recycling
Following endocytosis, the majority of internalized cargo
recycles back to the surface membrane (FIGURE 8) (549).
Experiments with antibody capture assays have demonstrated that KATP channels can be recycled in this manner
(538). Endocytic recycling of KATP channels represents a
potentially powerful mechanism for regulating their surface
density and availability for protection against stress events.
Many proteins pass through early endosomes in the recycling process. KATP channels likely follow this route, as
evidenced by the partial colocalization of internalized
Kir6.2 in pancreatic ␤-cells with the early endosome antigen
1 (EEA1) protein, which serves as a marker for this cellular
compartment (632). The term early endosome actually refers to two types of endosomes, namely, the sorting endosome and the endocytic recycling compartment (ERC)
(549). Cargo can be directed from the sorting endosome
194
G. Spatial Distribution of KATP Channels in
Ventricular Myocytes
The ventricular myocyte is a highly polarized cell. Many
channels and ion transporters are localized specifically to
the transverse (t)-tubules (749). Experiments with scanning
ion conductance microscopy have demonstrated that KATP
channels are concentrated at the Z-grooves, which are the
sarcolemma regions from which the t-tubules emanate
(457). From this observation, clustering of sarcolemmal
KATP channels is suggested, with a higher density of channels at the mouth of the t-tubule compared with the lateral
membrane. This suggestion is bolstered by the punctate
staining pattern in cardiomyocytes when performing immunocytochemistry with antibodies against KATP channel subunits (579). Polarized expression in a ventricular myocyte is
also evident at the end-to-end connection between cardiomyocytes (or the intercalated disc, ICD) and some channels,
such as connexins, are specifically targeted to this region
(749). Some channels, such as the cardiac Na⫹ channel
subunit Nav1.5, are targeted both to lateral membranes and
to the ICD and exist as two distinct pools of channels that
interact with specific scaffolding proteins (735). The lateral
Na⫹ channel exists as a complex with syntrophin and dystrophin, whereas the pool of Na⫹ channels in the ICD associates with desmosomal proteins (735). A similar “two-
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There is no agreement regarding the endocytic motifs required for endocytosis. Tyrosine-based motifs YXXØ,
where Ø denotes a hydrophobic amino acid, are often
found in membrane cargo and serve as a binding motif for
the ␮2 subunit of the AP2 adaptor complex, which is an
early step in clathrin-mediated endocytosis (781). Kir6.2
contains two such motifs: 258YhvI261 and 330YskF333. In
one study, mutating the first of these motifs (Y258A) had no
effect on endocytosis or surface expression, whereas mutating the second (Y330A) prevented endocytosis (537). In
another study, mutagenesis of this motif had no effect on
KATP channel endocytosis (89). The reasons for these discrepant findings are unclear, and further studies are needed
to determine whether the tyrosine-based motifs in Kir6.2
are relevant. Moreover, SUR2 contains several tyrosinebased motifs; none of these has been studied to date. Dileucine motifs are also involved in endocytosis and intracellular targeting. The [D/E]XXXL[L/I] motif in cargo proteins
binds mainly to the ␴2 subunit of the AP2 adaptor complex,
although variations of this motif can occur (459). Kir6.2
has one such motif (352DhsLL356), and SUR2 has none. In
one study, mutagenesis of the lysines at positions 355–356
prevented endocytosis of Kir6.2, either when expressed
with SUR1 or SUR2 (363). In another study, the same mutation had no effect on KATP channel endocytosis, but it did
increase surface expression, possibly as a result of enhanced
recycling (537). The concept that KATP channel endocytosis
is solely dependent on Kir6.2 (and embedded signals) is
likely too simplistic and has recently been challenged by the
finding that SUR1 undergoes endocytosis independent of
Kir6.2 (89). Clearly, much remains to be done before a
better understanding is reached regarding the mechanisms
and signals involved in KATP channel endocytosis.
directly and rapidly (⬍2 min) to the surface membrane, to
late endosomes and/or to the long-lived organelle, the ERC.
KATP channel recycling occurs at a time scale of 10 –15 min
(538), which argues against direct recycling to the membrane. EHD1 (also named Rme1) is a trafficking protein
that controls several recycling steps, including the exit of
cargo from the ERC to the surface membrane (590). A
dominant negative EHD1 construct (EHD1-G429R) was
reported in a single study to slow the recycling of the transferrin receptor, but not of KATP channels, suggesting that
KATP channels do not utilize this slow recycling pathway
(363). There may be a role for late endosomes in KATP
channel recycling. At steady state, KATP channels containing SUR1 are mainly expressed on the cell surface, whereas
many SUR2-containing channels are localized to intracellular vesicular compartments that are positive for the late
endosomal/lysosomal marker, LAMP2 (47). Since the halflives of SUR1 and SUR2 channels are similar, the SUR2containing KATP channels are most likely not directed to
this pathway for degradation (47). It is known that recycling to the membrane is possible through late endosomal
and lysosomal trafficking pathways (654), but it is not yet
clear whether KATP channels are directed via this pathway.
More experimentation is needed to determine the mechanisms by which KATP channels traffic through the endocytic
recycling pathway. This process may be more complex than
anticipated, as suggested by a recent finding that chamberspecific subcellular mechanisms may exist in cardiac myocytes (18).
KATP CHANNELS IN CARDIOPROTECTION
pool” model is possible for KATP channels as suggested by
the finding that dystrophin is required for the cardioprotective function of KATP channels in cardiomyocytes (280).
Moreover, there is emerging evidence that KATP channels
are expressed at a higher density at the ICD (356). The KATP
channels at the ICD do not appear to have distinct electrophysiological properties, but they interact and colocalize
with the desmosomal proteins plakophilin-2 and junction
plakoglobin. The functional roles for KATP channels at the
ICD are unclear, but they may be involved in cardiac electrical conduction (356) and with arrhythmias associated
with arrhythmogenic cardiomyopathy, which results from
mutations in desmosomal proteins (176).
KATP channels are fairly stable proteins. Pulse-chase experiments have demonstrated that SUR1 is stable when expressed alone, but that Kir6.2 is rapidly degraded with a
half time of ⬃30 min. When Kir6.2 is expressed with SUR1,
the channel complex has a half-life of ⬃8 h (138). Another
study has determined that the half-life of Kir6.2/SUR1
channels is ⬃15 h, whereas the Kir6.2/SUR2A might be
more stable with a half-life of ⬃20 h (47), despite their
colocalization with LAMP2, a marker of late endosomes
and lysosomes (see sect. VF). There is some evidence that
under certain conditions KATP channels can be diverted
to a lysosomal degradation pathway since lysosomal inhibitors prevents protein kinase C (PKC)-induced degradation (538). It is likely, however, that constitutive degradation occurs via the proteasome since nonstimulated
degradation is unaffected by the lysosomal inhibitor
chloroquine and prevented by MG132, which is an inhibitor of the proteasome (788, 858, 891).
I. The Physiological and Pathophysiological
Relevance of KATP Channel Trafficking
A clear role for leptin receptor signaling and glucose in KATP
channel trafficking in the pancreatic ␤-cell has recently
emerged. (109). Low extracellular glucose levels, associated
with fasting, increase the KATP channel surface density in an
AMPK-dependent pathway (504). Leptin, a hormone secreted by adipose cells, acts centrally in the hypothalamus
to control food intake. It has additional effects on the pancreatic ␤-cell to reduce insulin secretion. Recent data indicate that this action of leptin is attributed to stimulating
KATP channel to the surface membrane and that this pathway is controlled by AMPK, PKA, and Ca2⫹/calmodulindependent protein kinase kinase ␤ (109, 632).
The role of KATP channel subcellular trafficking has not
been studied extensively in the cardiovascular system, and
conflicting data exist. In guinea pig cardiomyocytes, hypoxia/reoxygenation before a sustained hypoxic episode (a cel-
VI. THE PHARMACOLOGY OF KATP
CHANNELS
There are many inorganic compounds that can promote or
inhibit KATP channel opening. These are respectively referred to as KATP channel openers (KCO) or inhibitors/
blockers. The pharmacological properties and a detailed
description of the structures of these compounds are beyond the scope of this text, and the reader is referred to
reviews for more information in these topics (200, 223,
645). The chemical structures of some of the compounds
are shown in FIGURE 9. Here, we will list examples of some
of these compounds commonly used in the literature (TABLE
3) and review some of the mechanism(s) by which they
affect KATP channel opening.
A. KATP Channel Inhibitors
An ion such as Ba2⫹ blocks the KATP channel by restricting
movement of K⫹ through the channel=s permeation pathway (779) and can therefore be referred to as a channel
blocker. The block of KATP channels by TEA and 4-aminopyridine (4-AP) most likely share the same mechanism
(416). Strictly speaking, compounds that inhibit KATP channel function through other mechanisms should be referred
to as KATP channel inhibitors (or antagonists), but we will
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H. Degradation
lular model of ischemic preconditioning) was shown to improve cellular survival and also to increase the amount of
Kir6.2 surface protein and the KATP channel current density
(93). Pharmacological preconditioning with epinephrine
had a similar effect in isolated rat ventricular myocytes
(824). The increased KATP channel density (presumably due
to enhanced trafficking) was mediated by AMPK, PKC␦,
PKC␧, and p38 MAPK (767, 824). PKC was also implicated
in the elevated levels of KATP channel subunits in sarcolemmal fractions after ischemia/reperfusion in the female rat
heart (199). The findings that PKC increases KATP channel
density in hearts is somewhat perplexing since most cellular
studies suggest that PKC causes KATP channel internalization or degradation (36, 363, 538). Ca2⫹/calmodulin kinase
II (CaMKII) may also have a role in KATP channel endocytic
recycling, particularly during cardiac ischemia. CaMKII inhibition was shown to increase the KATP channel surface
density, which was linked to improved ventricular myocyte
survival during ischemia (495). A subsequent study demonstrated that CaMKII interacts with and phosphorylates the
Kir6.2 subunit (at Thr-180 and Thr-224) to promote endocytosis (449, 741). Although some studies suggested that
KATP channel surface density is increased with cardiac ischemia (47, 199), it is tempting to speculate that prolonged or
severe ischemia that is associated with an increased cytosolic Ca2⫹ may be associated with KATP channel endocytosis,
mediated by a Ca2⫹-induced activation of CaMKII. This
possibility remains untested.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
CH3
H3C
CH3
HN
CH3
S
HN
CH3
HN
O
C
HN
N
CH3
O
O
O
O
N
S
H3C
H3C
S
O
Cl
S
HN
O
H3C
N
Pinacidil
N
N–
Diazoxide
Na+
HMR 1098
NH
N
H
O
Tolbutamide
Cl
O
O
O
H
N
CH3
S
O
O
O
Cl
H
N
O–
H3C
OH
Glibenclamide
H3C
O
O
5-Hydroxydecanoate
FIGURE 9. Chemical structures of KATP channel openers and blockers. Chemical structures are shown
for compounds that promote KATP channel opening [pinacidil (4660), diazoxide (2911), and HMR 1098
(21436283)] or inhibit KATP channel activity [glibenclamide (3368), tolbutamide (5304), and 5-hydroxydecanoate (1758)]. The structures were obtained from the ChemSpider database (http://www.chemspider.com/), and the numbers in brackets refer to the compounds= ChemSpider IDs.
interchangeably refer to them as inhibitors and blockers.
The most commonly used class of KATP channel inhibitors
(for the treatment of type II diabetes) is the hypoglycemic
sulfonylureas, which includes tolbutamide and glibenclamide. One of the first studies to suggest that tolbutamide
may affect K⫹ fluxes in the pancreatic ␤-cell was made in
the late 1970s with 86Rb⫹ flux assays (343). Soon after its
discovery in pancreatic ␤-cells (135), the KATP channel was
identified as the receptor for sulfonylureas (193, 766). All
types of KATP channels are now known to be inhibited by
sulfonylureas (e.g., tolbutamide and glibenclamide). The
sensitivities of diverse KATP channels to sulfonylureas differ;
for example, the KATP channels in the endothelium, vascular smooth muscle, and the cardiac conduction system are
more efficiently blocked by tolbutamide than the KATP
channel in the atrium or ventricle (TABLE 3). Other compounds also inhibit KATP channel function, including certain saturated fatty acids, such as the decanoic acid, 5-hydroxydecanoic acid (5-HD), which blocks the “ventricular”
Kir6.2/SUR2A channel with an IC50 of 0.2–30 ␮M in inside-out patches (497, 609). 5-HD also blocks KATP channels in mitochondria (262) with an IC50 value of 45–75 ␮M
(386). 5-HD may have complex actions, since the compound blocks ventricular KATP channels in isolated membrane patches, but is less effective in intact cells (497). 5-HD
is readily activated to 5-HD CoA, which is taken up into the
mitochondrial matrix and is metabolized by the ␤-oxidation pathway, albeit with slow kinetics (320 –322). 5-HD
196
also inhibits ␤-oxidation of other fatty acids (320), which
will affect cardiac energy metabolism. Other compounds
can also inhibit KATP channel function. For example, HMR
1098 is often used as a selective cardiac sarcolemmal KATP
channel blocker (199, 512, 539), but a recent systematic
study demonstrated that the compound affects various
classes of KATP channels (921). Care should therefore be
employed when using any of these compounds experimentally.
1. Where do sulfonylureas bind?
Sulfonylureas bind to SUR1 with high affinity. The Kd for
glibenclamide binding is ⬃0.5–10 nM (4, 186). In contrast,
the sulfonylurea binding affinity for SUR2x is somewhat
lower. The Kd for glibenclamide binding to SUR2A and
SUR2B is similar at ⬃30 –300 nM (186, 674, 675). When
coexpressed with Kir6.1, however, the SUR2B binding affinity increases from 32 to 6 nM (674). Higher sulfonylurea
concentrations (3- to 7-fold) are needed to inhibit channel
function (186, 674), and simultaneous occupancy of four
binding sites may be needed for channel inhibition (674).
The distal 42 amino acids, which is the only difference
between these two SUR2x splice variants, are not involved
in binding, since a chimeric SUR2 construct in which this
COOH-terminal region was replaced with that of SUR1 did
not have a higher sulfonylurea binding affinity (186). The
high-affinity sulfonylurea binding site was identified by gen-
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H
N
KATP CHANNELS IN CARDIOPROTECTION
erating chimeras between the high (SUR1) and low
(SUR2A) affinity receptors. SUR2A became highly sensitive
to tolbutamide inhibition when replacing its transmembrane domains 14 –16 with that from SUR1 (26). Mutating
a single residue in this region of SUR1 TMD2 (S1237) was
sufficient to prevent high-affinity tolbutamide inhibition.
Conversely, exchanging the corresponding residue in
SUR2B for a serine increases the affinity of glibenclamide
binding 5–10 times (314, 518). The sulfonylurea binding
pocket involves other regions of the protein as well. Deletion analysis has defined regions dispersed throughout SUR
that influence glibenclamide binding, including the cytosolic loop betweenTMD0 and TMD1, and the binding pocket
is mostly likely only revealed in the correctly folded heterooctameric KATP channel (563).
Intracellular nucleotides modulate the degree of KATP channel inhibition by sulfonylureas. The effect of MgADP is
most striking, and interestingly, the effect on different types
of KATP channels is opposite in nature. In the pancreatic
␤-cell, MgADP increases the efficiency by which tolbutamide inhibits the KATP channel by 10-fold (286, 707, 947).
Chimeric constructs made from SUR1/SUR2 identified a
region of SUR1 that includes transmembrane (TM) regions
8 –11 as being important in the ability of MgADP to potentiate sulfonylurea inhibition (659). One possibility is that
sulfonylureas impair the ability of MgADP to stimulate
Kir6.2/SUR1 channel activity, and consequently that the
inhibitory effects of ADP on Kir6.2 now predominate
(286). This may happen either by displacing MgADP from
its binding site, or by preventing intramolecular transduction of the stimulatory effect of MgADP (659). In SUR2containing KATP channels, however, MgADP impairs the
ability of sulfonylureas to inhibit KATP channel function
(313, 711, 842). For example, the SUR2A-based cardiac
KATP channel is half-maximally inhibited by 0.5 ␮M glibenclamide when recordings are made in the absence of ADP.
However, in the presence of 100 ␮M MgADP, glibenclamide is ineffective, even at concentrations as high as 300
␮M glibenclamide (842). Moreover, glibenclamide inhibition of whole-cell KATP channel current is more effective
when ADP is absent from the pipette solution (842). These
data might explain the finding that that sulfonylurea block
of cardiac KATP channels is impaired (or even prevented)
under conditions of metabolic inhibition (228, 842).
B. KATP Channel Openers
Examples of KCOs include nicorandil, minoxidil, pinacidil,
cromakalim, and diazoxide. Several classes of KCOs exist
(200), and electrophysiologically, they can be classified into
distinct groups (801). Some KCOs, which includes pinacidil, cromakalim, and derivatives, decrease the sensitivity of
1. Where do KATP channel openers bind?
KCOs act on the SURx subunit as demonstrated by coexpression studies in Xenopus oocytes, where Kir6.1 currents
were shown to be activated by diazoxide only when coexpressed with SUR1 (15). The SURx isoform present correlates with the channel=s pharmacological profile. For example, channels containing SUR1 are strongly activated by
diazoxide, but not by cromakalim or pinacidil (283, 284,
598). In contrast, SUR2A-containing channels respond
weakly to diazoxide under basal conditions, but are potently activated by pinacidil (284, 573, 731). Channels containing the SUR2B splice variant are sensitive both to diazoxide and cromakalim (711). Chimeric constructs between SUR1 and SUR2A identified transmembrane
domains (TMDs) 6 –11 and the first nucleotide-binding domain (NBD1) of SUR1 to be necessary for channel activation by diazoxide (39) (FIGURE 10).
2. Modulation of KCO activity by intracellular
nucleotides
Mutagenesis in either NBF1 (285) or NBF2 (739) impairs
the ability of diazoxide to activate Kir6.2/SUR1 channels.
Moreover, diazoxide stimulation of pancreatic ␤-cell or
Kir6.2/SUR1 channel activity was found to require the presence of Mg2⫹ and hydrolyzable nucleotides, MgATP or
MgADP (479, 739). It has been suggested that the ability of
diazoxide to activate KATP channels is dependent on the
ATPase activity of the SURx NBF domains (711) and that
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2. Modulation of sulfonylurea inhibition by
intracellular nucleotides
the KATP channel to ATP, resulting in increased channel
opening at a given level of cytosolic ATP. A compound in
this group, pinacidil, does not activate SUR1-containing
KATP channels (such as in the pancreatic ␤-cell), but shows
little discrimination amongs cardiovascular KATP channel
subtypes (TABLE 3). KCOs in another group, including diazoxide and nicorandil, require the presence of intracellular
ADP for activity. Nicorandil, which is a nicotinamide nitrate derivative, has a complex pharmacological profile that
combines nitrate-like and KATP channel opening activities,
and the results obtained with this compound are not always
easy to interpret mechanistically. Another compound in this
group, the benzothiadiazine diazoxide has been studied extensively in the cardiovascular literature. It was originally
described as having vasodilatory activity (671), but it soon
became apparent that it also causes hyperglycemia (616,
878) by inhibiting insulin release from pancreatic ␤-cells
(344). We now know that these effects are due to KATP
channel activation in these tissues (755, 816). In fact, several subtypes of KATP channels have a high sensitivity to
diazoxide (K1/2 in the micromolar range; TABLE 3) (535,
594, 816, 946). KATP channels in some tissues, such as the
ventricle, are relatively insensitive to diazoxide under basal
conditions, but the channel is sensitized to the compound
under metabolically impaired conditions (151, 546).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
N
TMD0
TMD1
TMD2
Outside
1
2
3
4
5
1
2
3
4
5
6
1
2
3
4
5
6
Inside
O
O
S
Cl
HN
MgATP
N
FIGURE 10. Binding sites within SURx for a KATP channel opener. Compounds belonging to the type 3 class
of KATP channel openers, such as diazoxide, have a complex mechanism of action and binding. A chimeric study
between SUR1 (diazoxide-sensitive) and SUR2A (diazoxide-insensitive) subunits has revealed that diazoxide
binds SUR1 within a region that is composed of TMD 6 –11 and NBF1 (39). The corresponding SUR2A regions
do not permit diazoxide stimulation. Diazoxide activity additionally has an ADP-dependent component, which is
mediated by NBF2 and the COOH-terminal 42 amino acids of SUR1 and SUR2. Thus SUR1 may have two
diazoxide binding sites, whereas SUR2 may contain a single binding site composed of NBF2 and the COOH
terminus (546). It should be noted that the SUR2B (COOH-terminal 42 amino acids) has a high sequence
similarity with SUR1, which may explain its high diazoxide sensitivity relative to SUR2A (TABLE 3). Chimeric
studies between SUR1 and SUR2B revealed that KATP channel openers such as pinacidil, levcromakalin, and
P1075 interact with regions within SUR2, but not SUR1, which include transmembrane (TM) helixes 16 and
7 and the cytosolic linker between TM 13–14 (828).
diazoxide may potentially increase KATP channel activity by
stimulating the ATPase activity of the channel complex
(285). The difference in diazoxide sensitivity between
SUR2A and SUR2B is interesting and informative, since
these variants only differ from each other in the distal
COOH-terminal tail (42 amino acids). In an elegant study,
it was indeed found that the distal COOH-terminal tail is
necessary for channel activation (FIGURE 10), both by
MgADP and diazoxide (546). Each of the Kir6.2/SUR1,
Kir6.2/SUR2A, and Kir6.2/SUR2B channels was activated
by diazoxide, but the activation of Kir6.2/SUR2A was only
observed at elevated ADP levels. The importance of the
COOH terminus was demonstrated when swapping the distal COOH terminus of SUR2A with that of SUR1, which
formed a KATP channel that responded effectively to
MgADP and diazoxide (546). These data suggest that the
SUR2A COOH terminus might interfere with MgADP
binding to NBF2, which is why higher cytosolic ADP concentrations are needed before diazoxide will activate the
SUR2A-containing channel. Residues within NBF2 are also
important, as demonstrated by a recent study by the Light
group (219). They found that mutagenesis of a single amino
acid residue in the SUR1 NBF2 (S1369) to the corresponding positively changed residue of SUR2 (K1337) is sufficient
to decrease the ATPase activity and to prevent diazoxideinduced activation of the mutant SUR1 channel in the absence of ADP (219).
198
C. Issues With the Use of KATP Channel
Modulating Compounds
We have seen that the efficiency of commonly used KATP
channel openers and inhibitors depend on the levels of intracellular nucleotides, with MgADP playing a particularly
important role. Thus a potential for problems exists when
using these compounds to assess the role(s) of KATP channels in a setting of a changed metabolic status. This would
be particularly problematic during hypoxia and ischemia
when cellular MgADP levels are increased. For example,
increasing the cytosolic MgADP concentration renders glibenclamide ineffective as a KATP channel blocker (228, 842).
Similar problems exist with some of the KATP channel openers. Although diazoxide has almost no effect on the “ventricular” Kir6.2/SUR2A channels in excised patches in the
absence of MgADP (371), it is known to shorten the cardiac
action potential (118, 580, 694) (see sect. IXB2). As stated
in the preceding paragraph, one reason for these discrepant
observations is that diazoxide only becomes active when
MgADP is elevated (SUR2A/Kir6.2 channels become as
sensitive to diazoxide as SUR1/Kir6. 2 channels when 100
␮M MgADP is present in the “cytosolic” solution; Ref.
151). Thus care should be taken when using diazoxide as a
compound with specificity or selectivity for subtype(s) of
KATP channels. These issues have been discussed in a recent
review (125).
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H 3C
COOH
MgATP
KATP CHANNELS IN CARDIOPROTECTION
VII. DIFFERENT SUBTYPES OF KATP
CHANNELS IN THE CARDIOVASCULAR
SYSTEM
A. Ventricular KATP Channels
1. Biophysical properties of native channels
The conductance of the single KATP channel exhibits weak
inward rectification (inward currents are correspondingly
larger than outward currents). In general, the slope conductance is determined for inward currents at a linear region of
the current-voltage (I-V) relation. Slope conductance values
of the ventricular KATP channel in symmetrical high (140
mM) K⫹ concentrations have been reported to be 75– 80 pS
(38, 48, 317, 416). In the absence of nucleotides, the KATP
channel opens with a high (⬃0.82) Po (232). Opening occurs with a bursting behavior (359), with intraburst open
and closed times, respectively of ⬃1.8 ms and 0.15 ms at
⫺80 mV (38). The dwell-time kinetics are dependent on the
membrane voltage and to some extent also the K⫹ driving
force (938).
The Po of the ventricular KATP channel is strongly modulated by the presence of nucleotides at the cytosolic face of
a membrane patch (416, 607, 815). The ATP concentration
needed to produce half-maximal block (IC50) varies between studies, and values between 20 and ⬃100 ␮M have
been reported (TABLE 2). There is a large variation in reported IC50 values, even from the same laboratory; for example, the IC50 values for different patches from rat ventricular myocytes exhibit a 60-fold difference, ranging between 9 and 580 ␮M (232). Moreover, the channel=s ATP
sensitivity is not fixed. Even in the same patch, the IC50
value can change from 215 to 46 ␮M within minutes after
patch excision (127). Although the KATP channel can be
blocked by high cytosolic ADP levels, it is stimulated by
MgADP, and the concept has evolved that the channel is
regulated by the ATP/ADP ratio. For a more complete discussion of the nucleotide regulation of KATP channels,
please refer to section II.
2. Molecular composition
The current consensus is that the ventricular KATP channel
protein complex minimally consists of a Kir6.2/SUR2A
subunit combination. An argument in favor of this notion
includes the expression of Kir6.2 and SUR2A mRNA and
protein in ventricular tissue (117, 372, 579, 684). Knockdown of Kir6.2 and SUR2 expression by antisense oligonucleutides decreases expression of native ventricular KATP
channels (904). Likewise, overexpression of dominant-negative Kir6.x subunits impairs ventricular KATP channel
function (474, 810, 830, 936), and ventricular KATP channels are absent in knockout mice genetically deficient of
Kir6.2 or SUR2 subunits (763, 769). Heterologously expressed Kir6.2/SUR2A channels have properties similar to
native ventricular KATP channels, such as the single-channel
conductance, dwell-time kinetics, sensitivity to block by
intracellular ATP, and stimulation by intracellular MgADP
(38). Moreover, heterologously expressed Kir6.2/SUR2A
channels have a pharmacological profile similar to native
ventricular KATP channels, including their block by glibenclamide and stimulation by cromakalim and pinacidil (in
the presence of intracellular MgATP) and relative insensitivity to diazoxide when intracellular MgADP is absent (38,
151, 546). There are reports that Kir6.1 (525, 540, 565,
578, 881) and SUR1 (578) mRNA and protein are expressed in ventricular myocytes. Although genetic knockout of Kir6.1 does not appear to affect the whole cell ventricular KATP channel current (565), the roles of Kir6.1 in
ventricular function are not understood. There is a possibility that Kir6.1 may contribute to a novel small (21 pS)
conductance KATP channel in the ventricle, which has similar properties to the 80 pS channel, but has a high sensitivity to diazoxide (881). Thus the contribution of the “atypical” KATP channel subunits cannot be completely discounted, especially considering reports demonstrating
upregulation of Kir6.1 expression levels in the ventricle after treatment with KATP channel opening drugs or after
cardiac ischemia (74, 381). Please refer to section VA.
3. Physiological roles of ventricular KATP cardiac
channels
In patch-clamp experiments, there is little evidence for basal
or spontaneous opening of KATP channels in resting ventricular myocytes. Although some reports demonstrate that
KATP channel block with glibenclamide or tolbutamide
lengthens the ventricular action potential duration (118,
213), suggestive of constitutively active KATP channels,
most reports show that the ventricular action potential is
relatively insensitive to glibenclamide or 5-HD under basal
conditions (133, 400, 577, 747). Blockade of KATP channels
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Not only does glibenclamide become an inefficient KATP
channel blocker in metabolically impaired cells (230) and
diazoxide a more efficient opener (151), but each of the
KATP channel modulators also have unanticipated off-target effects (TABLE 3). For example, tolbutamide uncouples
oxidative phosphorylation of mitochondria (428). It may
also protect the ischemic myocardium by increasing glycolysis without increasing lactate production by promoting
the entry of pyruvate into the mitochondria (461), which
results in an ATP-sparing effect (476). Glibenclamide
blocks other types of channels, and most of the KATP channel modulators directly or indirectly affect mitochondrial
function (TABLE 3), including uncoupling of oxidative phosphorylation, blocking succinate dehydrogenase, and/or
serving as substrates for mitochondrial respiration. These
issues are discussed in more detail later (see sect. IXB7).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
with glibenclamide or HMR-1098, however, attenuates the
action potential duration shortening induced by KATP channel openers, metabolic inhibition, hypoxia, and ischemia in
a variety of animal models and experimental preparations
(TABLE 6), which gave rise to the concept that ventricular
KATP channels only open under conditions of metabolic
impairment. For a full discussion of this topic, please refer
to section IXB2. Recent data with genetic mouse models
have demonstrated that ventricular KATP channels do have
important physiological roles, including the provision of
tolerance to exercise and stress. They also contribute to the
action potential duration adaptation that occurs over a time
course of a few minutes upon changes in heart rate (see sect.
VIII).
1. Biophysical and pharmacological properties of
native atrial KATP channels
Soon after the identification of the ventricular KATP channel, KATP channels were also identified in the atria of guinea
pig (310) and human hearts (342). These channels are superficially similar to ventricular KATP channels with a unitary conductance between 52 and 80 pS (TABLE 2). They
exhibit bursting behavior with intraburst mean open and
closed times of 1.4 and 0.3– 0.6 ms, respectively (50, 342).
Atrial KATP channels are activated by hypotonic solutions
or by membrane stretch (50, 833). Atrial KATP channels
have a distinct pharmacology. Although the rabbit and
guinea pig atrial KATP channel is activated by 10 –500 ␮M
nicorandil (310, 485), rilmakalim (7 ␮M) and pinacidil
(100 ␮M) were described not to activate the atrial KATP
channel in the rabbit atrium (668). Pinacidil was found to
block the atrial KATP channel in other studies (TABLE 3). In
atrial appendages from rat heart, KATP channels are blocked
by glibenclamide with an IC50 value of 1.2 nM (50, 310)
and activated by low diazoxide concentrations (50, 237); these
are similar potencies as the high-sensitivity glibenclamide
block or diazoxide activation of pancreatic ␤-cell KATP channels (460, 703). Tolbutamide blocks rodent atrial KATP channels with high affinity (833), but the human atria KATP channel
is relatively insensitive to tolbutamide (945).
2. Molecular composition of atrial KATP channels
Neonatal rat atrial appendage cardiomyocytes were reported to express mRNA for Kir6.1, Kir6.2, SUR1A,
SUR1B, SUR2A, and SUR2B subunits (as determined by
RT-PCR) (50). A role for Kir6.x subunits is demonstrated
by the finding that overexpression of dominant-negative
Kir6 subunits suppress native KATP channels in rat atrium
(830). Moreover, KATP channels are absent in the atria isolated from Kir6.2⫺/⫺ mice (678). A side-by-side comparison
of mouse tissues revealed that SUR1 protein is predominantly expressed in the atrium (and to a lesser extent in the
200
3. Physiological roles of atrial KATP cardiac channels
Atrial KATP channels most likely have similar roles to those
in the ventricular myocardium, namely, protection against
stress responses and action potential duration adaptation to
sudden increases in the heart rate. If anything, the roles of
KATP channels in the atrium are likely to be more pronounced since atrial KATP channels are significantly more
sensitive to metabolic inhibition in atrial than ventricular
myocytes (642). An additional role for KATP channels has
been suggested in the release of atrial natriuretic peptide
(ANP) from atria. However, pharmacological data are inconsistent. Some studies demonstrated that KATP channel
block with tolbutamide and glibenclamide suppress the release of atrial natriuretic peptide (ANP) from rat and dog
atria in response to mechanical stretch (437) or heart failure
(107). Other studies, however, suggested that 100 ␮M tolbutamide increases the release of ANP from neonatal rat
atrial myocytes or intact atria in response to stretch or hypoxia (402, 886). Moreover, the stretch-induced ANP secretion is inhibited by KATP channel openers pinacidil or diazoxide (886). The mechanosensitive modulation of the
atrial KATP channel (833) by membrane stretch may well be
implicated in this process. Definitive evidence for a role of
KATP channels in ANP release from atria was obtained with
Kir6.2⫺/⫺ mice, in which volume expansion has a more
pronounced effect on the elevation of plasma ANP concentration and induction of hypotension compared with wildtype mice (678). Collectively, these data are consistent with
a role for mechanical stretch to open KATP channels, which
are linked to ANP secretion from the atria, which in turn
affects a variety of physiological end points, including vasodilation, anti-ischemic actions, and reduced hypertrophic
effects.
C. KATP Channels in the Specialized Cardiac
Conduction System
1. Biophysical and pharmacological properties of
native channels
The literature hints at the possibility that cardiac conduction system (CCS) KATP channels may have a unique molecular composition (which determines function and pharmacological properties). For example, although the AV nodal
KATP channel is superficially similar to the ventricular chan-
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B. Atrial KATP Channels
ventricle) (237). Moreover, the KATP channel current is virtually absent in atria from SUR⫺/⫺ mice, whereas the ventricular KATP channel is unaffected (237). The SUR1 composition of atrial KATP channels appears therefore to be
responsible for the unusually high diazoxide sensitivity in
this tissue (TABLE 3). It should be noted that this situation
may be unique to rodents since the differential sensitivity to
diazoxide in the atria and ventricles of dog and human heart
is less prominent (222, 922).
KATP CHANNELS IN CARDIOPROTECTION
Glibenclamide has no effect on the basal heart rate of isolated rat hearts (424) or the firing rate of SA nodal cells
isolated from rabbit hearts (318), suggesting that KATP
channels are constitutively closed. KATP channel openers
such as nicorandil and cromakalim, in contrast, decreases
the cardiac pacemaker rate, shortens the SA nodal action
potential and hyperpolarizes the membrane potential, and
may produce atrioventricular (AV) block (278, 697). In
inside-out membrane patches excised from rabbit SA node
pacemaker cells, cromakalim or pinacidil activates and glibenclamide blocks KATP channels (318). Levcromakalim also
shortens the action potential duration of rabbit Purkinje
fibers (502). We demonstrated that diazoxide (200 ␮M) is
more effective to activate mouse CCS KATP channels than
ventricular KATP channels, whereas levcromakalim had the
opposite profile (48). Thus CCS KATP channels may have a
different functional and pharmacological properties compared with the ventricular KATP channel.
2. Molecular composition
A large-scale transcriptional analysis of mouse cardiac tissue showed that Kir6.1, Kir6.2, and SUR2 mRNAs were
expressed at higher levels in the ventricle compared with the
SA node or AV nodes (540). In the dog and mouse, we
found elevated expression of Kir6.1 mRNA and protein
(and decreased expression of Kir6.2) in the CCS relative to
the ventricle (48). A role for Kir6.1 in cardiac conduction is
underscored by the finding AV block is observed in radio
telemetry recordings of the ECG in Kir6.1⫺/⫺ mice (565).
Although the role of Kir6.1 and the mechanism(s) by which
Kir6.1 subunits may contribute to cardiac conduction are
presently unclear, clinical data demonstrate that a strong
association exists between genetic variation in KCNJ8 and
the risk of Brugada syndrome, J wave syndromes, ventricular fibrillation, and atrial fibrillation (see sect. X). An important role also exists for Kir6.2, since the Kir6.2⫺/⫺ mice
lack SA nodal pinacidil-activated KATP channel currents,
and hypoxia-induced bradycardia is mitigated in the knockout mice (248). We found the contactin 2-positive CCS
mouse myocytes to be enriched for SUR2B, whereas SUR1
was undetectable (48). The elevated SUR2B expression
might account in part for the enhanced sensitivity of the
mouse CCS to diazoxide (546). The possibility of diversity
of KATP channel subunit expression in various regions of the
CCS (e.g., proximal vs. distal) is real, but has not been
formally investigated.
3. Physiological and pathophysiological roles of KATP
channels in the specialized cardiac conduction
system
KATP channels appear to be expressed in all regions of the
cardiac conduction system, including the SA node, AV
node, and the specialized Purkinje network. Their activity
affects the functional properties of these cells (415, 502,
696). For example, hypoxia produces bradycardia, which is
mediated by KATP channel opening (248, 498). The conduction slowing and AV block that occurs with hypoxia in
Langendorff-perfused rabbit hearts is also mediated by
KATP channels since it can be prevented by glibenclamide
(698). Glibenclamide has also been described to reduce the
intramyocardial conduction delay induced by ischemia in
dog (61) and mouse (48) heart, and to decrease ischemiainduced transmural conduction block in a canine wedge
preparation (633). Similarly, glibenclamide prevents the increased longitudinal resistance (electrical uncoupling) in an
isolated rabbit septal preparation during ischemia (787)
and prevents the subendocardial conduction delay produced by ischemia in an isolated, arterially perfused canine
interventricular septal preparation (576). Thus CCS KATP
channels are likely to participate in ischemia-induced conduction disturbances and precipitate life-threatening arrhythmias, and they may therefore represent novel therapeutic targets.
D. KATP Channels in the Vascular Smooth
Muscle
1. Biophysical properties of native channels
Vasodilators such as diazoxide (671) and pinacidil (21) hyperpolarize smooth muscle cells due to an increased K⫹
conductance (345). The initial finding that pinacidil activated KATP channels in the heart (19) suggested the possi-
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nel, it was reported to have a smaller conductance (415).
Similarly, myocytes from the rabbit sinoatrial (SA) nodal
and Purkinje myocytes also have a smaller unitary conductance (52– 60 pS; cf. ⬃70 – 80 pS in the ventricle; TABLE 2).
Moreover, the ATP sensitivity of rabbit Purkinje KATP
channels is lower than that of the ventricular channel (48,
502). Using a novel reporter mouse that expresses EGFP
specifically in the CCS (628), we examined the properties of
CCS KATP channels and found significant and biologically
relevant differences between CCS and ventricular KATP
channels (48). Aside from a smaller unitary conductance,
we observed differences in their nucleotide regulation. Not
only were the CCS KATP channels less sensitive to inhibitory
ATP, but they were more readily activated by intracellular
MgADP. Ventricular KATP channels were characteristically
stimulated by lower MgADP concentrations (227), but inhibited as the ADP concentration was increased (416). In
contrast, the CCS KATP channels were stimulated by
MgADP, but not inhibited within the concentration range
examined. Half-maximal activation occurred at 84 ⫾ 3.7
␮M MgADP (48). These results suggest that CCS KATP
channels are preferentially opened by alterations in intracellular nucleotides, which may be a pathophysiologically
relevant finding given the importance of ventricular CCS
and Purkinje-ventricular junction (PVJ) in the generation of
ischemia-induced arrhythmias (392) (see sect. IXB4 for further discussion of this topic).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
2. Molecular composition
Transcripts of the KATP channel subunits Kir6.1 and SUR2B
are highly expressed in vascular tissue, whereas SUR1 and
SUR2A mRNAs are expressed at lower levels (117, 372,
374, 382). Kir6.2 mRNA is present in several types of
smooth muscle (277, 378, 395, 662, 743, 799). However,
despite the presence of the transcript, the Kir6.2 protein is
not expressed [e.g., in human coronary artery (907)] and
the possibility of posttranscriptional regulation of Kir6.2
expression must be considered. Moreover, genetic deletion
of Kir6.2 in mice abolishes KATP channels in the cardiac
ventricle, but not in the aorta, further demonstrating that
this subunit has little role in the vascular smooth muscle of
the mouse (769). Heterologous coexpression of Kir6.1 and
SUR2B subunits gives rise to channels with functional and
pharmacological properties that recapitulate smooth muscle KNDP channels [e.g., a single-channel conductance of
⬃33 pS, a requirement for intracellular NDPs for channel
opening, and a relative insensitivity to block by ATP (888)].
Moreover, both Kir6.1⫺/⫺ and SUR2⫺/⫺ mice lack KATP
channel activity in aortic smooth muscle myocytes (115,
565), lending further support to the idea that smooth muscle KATP channels are composed of a Kir6.1/SUR2B subunit
combination. Both mouse models additionally exhibit incidences of spontaneous coronary vasospasm, resembling human Prinzmetal angina. Interestingly, however, this phenotype is not eliminated when reintroducing SUR2B specifically into smooth muscle in the SUR2⫺/⫺ background,
suggesting that the coronary vasospasm may arise from a
smooth muscle-extrinsic process (417).
202
3. Physiological roles of vascular KATP channels
The vasculature, particularly the small resistance arterioles,
is under constant tone to regulate blood flow to the periphery and to organs. The vascular tone is not constant and is
subject to moment-to-moment variations to regulate blood
as needed. In some tissues, such as the heart and the brain,
spontaneous vasodilation and vasoconstriction may occur
upon changes in metabolic demand (named autoregulation
of blood flow). Vascular tone and blood flow may also be
regulated by a number of vasoactive substances such as
calcitonin gene-related peptide, adenosine or prostacyclin
(which cause vasodilation) or angiotensin II, vasopressin, or
endothelin (which cause vasoconstriction). Opening of
KNDP channels hyperpolarizes smooth muscle cells, which
leads to less Ca2⫹ entry, vasodilation, and increased blood
flow (649) (FIGURE 11). The contribution of KNDP channels
to regulating the membrane potential of smooth muscle
cells (and thus blood flow) increases as the coronary diameter decreases along the vascular bed (7, 106, 198, 447,
587, 691), consistent with a significant role for KATP channels in the smaller resistance vessels (686). Their contribution to the regulation of coronary function was first identified by the vasodilatory actions of KATP channel openers
(290, 649, 682) and the vasoconstrictive effects of KATP
channel blockers (424). Thus an essential role for coronary
KATP channels was identified in the vasodilatory responses
of adenosine (155, 649), angiotensin II (64), hypoxia (161,
649), exercise (192), and metabolic demand (33, 34, 427),
and it is now accepted that KATP channels are essential for
maintaining basal coronary vascular tone in vivo (454,
686).
E. KATP Channels in the Endothelium
1. Biophysical and pharmacological properties of
endothelial KATP channels
KATP channels are not only present in the coronary smooth
muscle cells, but also in the coronary endothelium (380,
469, 508, 708, 851, 946). The endothelial KATP channels
differ from the vascular channels in terms of their molecular
composition, pharmacological profiles, biophysical properties, and functional roles. Both cells types express many
different ion channels (221, 388, 601) with diverse roles in
the regulation of blood. In resistance vessels, the endothelium may regulate smooth muscle contraction (and thus
blood flow and blood pressure) by 1) direct effects on the
smooth muscle membrane potential (Em) through electric
coupling via gap junctions and/or 2) by releasing of vasoactive substances in response to various stimuli. Ion channels
(including KATP channels) are involved in both of these
processes. Endothelial cells have fairly negative resting Em
of between ⫺80 and ⫺30 mV, depending on their origin
and treatment (culturing vs. freshly isolated, etc.) (2). There
are reports of diversity within a single cell population. For
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bility that KATP channels were also present in vascular
smooth muscle. Indeed, patch-clamp recordings demonstrated that single KATP channels are present in excised
patches from smooth muscle cells enzymatically dissociated
from rabbit and rat mesenteric arteries (755). Single KATP
channels had a fairly low open probability, were inhibited
by cytosolic ATP in the submillimolar range, and had a
unitary conductance of ⬃135 pS. The channels were activated by pinacidil, diazoxide, and cromakalim and blocked
by glibenclamide (755). In subsequent studies, two types of
vascular KATP channels have been described: either with a
small/medium (10 –50 pS) or large (135–200 pS) conductance (the reader is referred to an excellent review on this
subject, see Ref. 649). The small/medium conductance
channels require the cytosolic presence of nucleoside
diphosphates (NDP) for opening and are therefore often
referred to as KNDP channels. The vascular KNDP channels
can be activated by metabolic inhibition (75, 919); cellular
ATP depletion; hypoxia (154); KATP channel openers such
as levcromakalim (75), pinacidil (274, 413), and nicorandil
(377, 414, 853); and inhibited by KATP channel blockers
such as glibenclamide (75, 853, 919). The presence of Ca2⫹
appears to be required for KNDP channel opening (377,
853). Vascular KNDP channels open in bursts with at least
two open states and several closed states (414, 853).
KATP CHANNELS IN CARDIOPROTECTION
example, bovine aortic endothelial cells have a bimodal
distribution, with some cells having a resting potential
around ⫺25 mV whereas others are at ⫺85 mV (558).
Interestingly, transitions between these two states can occur
due to the N-shaped I-V relationship of endothelial cells.
The relationship between the Em and extracellular K⫹ is
well described by the Nernst equation (52 mV/decade
change in [K⫹]o), with some deviation at lower K⫹ concentrations, suggesting a strong basal K⫹ conductance (2). Indeed, most published studies report the presence of inward
rectifier K⫹ channels (2, 602).
2. Molecular composition
The molecular composition of endothelial KATP channels
remains to be fully characterized. Guinea pig cardiac capillaries express Kir6.1, Kir6.2, and SUR2B mRNA (705).
These subunits are also present in human coronary artery
endothelial cells, both at the mRNA and protein level (907).
In rats, the endothelial KATP channel was described to be of
a SUR2B/Kir6.1 subtype (793). Pulmonary artery endothelial cells isolated from Kir6.2⫺/⫺ mice have an impaired
response in membrane potential changes and ROS generation associated with shear stress (547). Moreover, trans-
3. The physiological role of endothelial KATP channels
Prevailing evidence suggests that KATP channels in the coronary microvasculature are responsible for maintaining a
constant blood flow to the myocardial tissue (387, 388).
They regulate coronary flow alterations in response to metabolic demand (160) and the maintenance of flow in response to changes in blood pressure (454, 589). There is
evidence that endothelial KATP channel opening may improve pressure overload-induced cardiac remodeling in rats
by protecting endothelial function (793). Their contribution increases as the coronary diameter decreases along the
vascular bed, consistent with a significant role for KATP
channels in the smaller resistance vessels (7, 447, 587, 686,
691). In the vascular smooth muscle cells, KNDP channels
regulate the membrane potential and the contractile state of
the smooth muscle myocytes, but endothelial KATP channels
add another dimension to the regulation of blood flow (FIGURE 11). For example, endothelial KATP channels mediate
coronary microvascular dilation to hyperosmolarity (380).
An important link to adenosine and NO generation also
appears to exist. For example, in the isolated perfused
guinea pig heart endothelial KATP channels have been implicated in the response to adenosine and extracellular ATP
(488). With the use of cannulated microvessels isolated
from porcine heart, it was confirmed that the vasodilatory
effect of adenosine (particularly at lower doses) is mediated
by endothelial KATP channels (469). Adenosine-induced vasodilation is also attenuated by L-arginine analogs that inhibit NO synthesis (488) or by the eNOS inhibitor NGmonomethyl-L-arginine (L-NMMA) (469), suggesting a
connection between KATP channels and NO synthesis (see
also Ref. 266). There is additional strong evidence that the
well-known hypoxic vasodilation in the coronary system is
mediated exclusively by KATP channels present in the coronary endothelium (508). Endothelial KATP channels may
also contribute significantly to the pharmacological profile
of KATP channel agonists. For example, in addition to their
well-described effects in smooth muscle, KATP channel
openers may directly act on the endothelium (528), and
endothelium removal decreases the sensitivity of some arteries to KATP channel openers (395). KATP channels may
also regulate the release of the vasoactive substances such as
the vasoconstrictor endothelin-1 (267). Endothelial KATP
channels may have a role in [Ca2⫹]i homeostasis, but data
are conflicting. For example, some studies show that KATP
channel openers cause a transient increase in intracellular
Ca2⫹, but this increase was not temporary related to mem-
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The description of endothelial KATP channel properties and
molecular composition is scant, but convincing. The majority of reports demonstrate that KATP channel openers
(levcromakalim, rimakalim, pinacidil, and minoxidil) cause
membrane hyperpolarization of various magnitudes in endothelial cells from rabbit aorta, guinea pig isolated capillary fragments and human coronary artery (426, 477, 478,
907; but see Ref. 558). In whole cell patch-clamp experiments performed with freshly isolated cerebral microvascular and rat aortic endothelial cells, a glibenclamide-sensitive
K⫹ current is activated by intracellular dialysis with low
[ATP], with metabolic inhibition or by pinacidil (390). Essentially similar results were found with freshly isolated
rabbit aortic endothelial cells (426) and isolated guinea pig
capillaries (705). Basal KATP channel activity is suggested by
the finding that in bovine pulmonary endothelial cells glibenclamide inhibits a proportion of the current (in the absence of KATP channel agonists or metabolic inhibition)
(105). Interestingly, the glibenclamide-sensitive component
of the IV relationship is hugely increased when endothelial
cells are adapted to flow conditions (likely to better represent a physiological setting compared with cells grown under static culturing conditions) (105). Effects of KATP channel blockers on the Em have not been investigated. At the
single-channel level, one report suggests the presence of a 40
pS KATP channel, which is blocked by cytosolic ATP and
glibenclamide, in isolated patches of cerebral microvascular
endothelial cells (390). Another reports the presence of two
types of channels (25 and 150 pS), both being blocked by
cytosolic ATP or glibenclamide (426). Endothelial KATP
channels appear to be exquisitely sensitive to diazoxide and
tolbutamide (426, 477, 478) (TABLE 3).
genic expression of Kir6 dominant negative subunits specifically in the endothelium lead to impaired coronary artery
function, elevated blood pressure, and defects in ET-1 release (536). SUR1 does not appear to be expressed at significant levels under physiological conditions, but there is
evidence of enhanced endothelial SUR1 expression following stroke, where it may participate in cerebral edema
(744).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Vascular
smooth
muscle
KCO
Hypoxia
Adenosine
VIP
Endothelial cell
+
K+
Em
Em
Ca2+
Ca2+
+
KCO
Hypoxia
Adenosine
NO
ET-1
–
Relaxation
brane hyperpolarization (478), whereas other studies with
levcromakalim found no effect on intracellular Ca2⫹ in rabbit aortic endothelial cells (426). KATP channel block with
glibenclamide was described to increase Ca2⫹i in pulmonary artery endothelial cells (864). The reasons for these
conflicting data are unclear, and further studies are needed
to clarify the mechanisms by which KATP channels affect
endothelial function.
F. KATP Channels in Mitochondria
1. Biophysical and pharmacological properties of
native channels
A mitochondrial KATP channel has first been described in
the inner membrane of fused giant mitoplasts from rat liver
204
Mitochondrial KATP channels are often studied nonelectrophysiologically by using surrogate assays such as K⫹ flux measurements, with fluorescent dyes (44, 263, 636) or with 86Rb⫹
fluxes (55). A recent development is the use of Tl⫹-sensitive
fluorophores (877). In contrast to the weak effect of ATP on
the channel in patch-clamp studies (see above), K⫹ fluxes of
the reconstituted mitochondrial KATP channel in liposomes are
efficiently inhibited by MgATP (IC50 of 45 ␮M), MgADP
(IC50 of 280 ␮M), and glibenclamide (IC50 of 50 nM). Interestingly, Mg2⫹ is required for ATP inhibition, whereas glibenclamide is not effective when Mg2⫹ is present (636), which is a
situation unlike that found for plasma/sarcolemmal KATP
channels. In liposomes, the ATP-inhibited K⫹ fluxes can be
restored by diazoxide and cromakalim. Pharmacological
properties of mitochondrial KATP channels are listed in TABLE
3. It should be pointed out that there is not universal agreement in the literature on the presence and role of these channels; some investigators were unable to find evidence of KATP
channels in mitochondria (53, 91, 159, 309). For a lively discussion on whether the existence of mitochondrial KATP channel is a fact or whether it represents fiction, please refer to a
recent debate manuscript (260). For further reading on channels in the mitochondrial inner membrane, please refer to a
recent review (944).
2. Molecular composition
Biochemically, 125I-glibenclamide labels a 28 kDa protein in bovine heart mitochondria (774), whereas the
fluorescent probe BODIPY-glibenclamide labels a 64
kDa protein in brain mitochondria (44). The identity of
these proteins remains unclear. Some reports demonstrated that conventional KATP channel subunits, Kir6.x,
and SURs are present in mitochondria, but others found
this not to be the case (TABLE 5). Likely reasons for these
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FIGURE 11. Possible roles of KATP channels in the vascular smooth
muscle and in the endothelium in the regulation of blood flow. KATP channels in the vascular smooth muscle cells (VSM) regulate the membrane
potential and the contractile state of smooth muscle cells. Specifically,
opening of smooth muscle KATP channels by triggers such as KATP channel
openers, hypoxia, adenosine, and vasoactive intestinal peptide (VIP)
causes membrane hyperpolarization, which prevents Ca2⫹ entry through
voltage-gated Ca2⫹ channels and prevents vasoconstriction (or causes
vasodilation). A speculative role of KATP channels in the endothelium is
presented. Chemical transmitters, shear stress, and hypoxia may elevate
cytosolic Ca2⫹ activity in endothelial cells, which may stimulate the secretion of vasoactive factors through an action on enzymes such as nitric
oxide (NO) synthase and phospholipase A2. The elevated Ca2⫹ may regulate the secretion of NO, which causes feedback inhibition of the ET-1
production (77) and directly contributes to vasodilation of the vascular
smooth muscle. In nonexcitable cells (such as endothelial cells), opening of
Ca2⫹-activated K⫹ channels is required to prevent membrane depolarization when Ca2⫹ influx occurs. It is possible that KATP channel opening (by
hypoxia, bradykinin, and adenosine) may achieve a similar function, but this
possibility remains to be investigated.
mitochondria (376). The channel has a small (9pS) conductance, and is weakly blocked by ATP (IC50 of ⬃800 ␮M)
and also blocked by 4-aminopyridine and glibenclamide.
The literature is not consistent, however. Other studies also
reported the reconstituted channel to have a low sensitivity
to MgATP block (IC50 ⫽ 335 ␮M), with incomplete block
at 1 mM MgATP (585, 918), but with the channel having a
unitary conductance of 24 –105 pS (54, 585, 636, 918)
(TABLE 4). Patch clamping of the inner mitochondrial membrane of human T-lymphocytes also demonstrated the presence of mitochondrial KATP channels (153). The reconstituted mitochondrial KATP channel is activated by superoxide, isoflurane, and diazoxide and inhibited by 5-HD and
glibenclamide (54, 585, 918). Not all studies, however, are
in agreement with these findings. In rat brain, for example,
reconstitution of the purified inner membrane from rat
brain mitochondria into a planar lipid bilayer yields mitoKATP channels with a large (⬃220 pS) single-channel conductance that is not blocked by 5-hydroxydecanoic acid
(113). Mitochondrial KATP channels were not observed in
all electrophysiology studies (17).
KATP CHANNELS IN CARDIOPROTECTION
Table 4. Properties of mitochondrial KATP channels measured by patch clamping or in lipid bilayers
Preparation
Technique
Unitary
Conductance
ATP
5-HD
Diazoxide
Comment
Reference
Nos.
Rat liver fused
mitoplasts
Patch
clamping
9.7 pS (33/100 mM
K⫹ gradient)
IC50 ⬃800 ␮M
No data
No data
Bovine brain
mitoplasts
Planar lipid
membrane
30 pS (1/1 M K⫹
gradient)
IC50 ⬃45␮M1
No data
No data
Human Tlymphocyte
mitoplasts
Patch
clamping
15 pS (150/150
mM K⫹ gradient)
⬃50% inhibition
by 12mM
ATP
1mM 5-HD
irreversibly blocks
by 50%
No effect by 50–500
␮M diazoxide
Rat ventricle
Planar lipid
membrane
26–105 pS (150/
150 mM K⫹
gradient)
IC50 ⬃335
␮M2
Blocked by 100 ␮M
5-HD
Activated by 50 ␮M
diazoxide
585
Bovine heart
Planar lipid
membrane
56 pS (150/150
mM K⫹ gradient)3
⬃70% block by
1mM ATP2
Blocked by 10–100
␮M 5-HD
Activated by 10 ␮M
diazoxide
918
Bovine heart
Planar lipid
membrane
104 pS (50/150
mM K⫹ gradient)
Inhibition by
500 ␮M
MgATP
No data shown
No data shown
54
Rat brain
Planar lipid
membrane
219 pS (50/450
mM K⫹ gradient)
Blocked by 2.5
mM MgATP
150 ␮M HD does
not inhibit
No data
113
Channels detected
in 1/3 of
patches
376
636
Weakly outward
rectifying
153
discrepancies include the purity of the mitochondrial
fractions (with possible contamination of other intracellular membrane compartments) and the relative lack of
specificity of many commercial antibodies against Kir6.x
and SURx subunits. For example, immunoprecipitates
from isolated heart mitochondria obtained with antiKir6.1 commercial antibodies yield proteins with molecular sizes of 48 and 51 kDa. MS/MS analysis of these
proteins demonstrated them to be mitochondrial isocitrate dehydrogenase and NADH-dehydrogenase flavoprotein 1 (241). When expressed in HEK-293 cells, channels with a Kir6.1/SUR1 subunit combination have a
similar pharmacological profile to mitochondrial KATP
channels, namely, activation by diazoxide, block by
5-HD, and relative insensitivity to HMR-1098 (512). Immunofluorescence experiments, however, fail to detect
Kir6.1 or Kir6.2 in mitochondria of cardiac myocytes,
either after viral delivery (718) or with cardiac-specific
transgenic overexpression (810). An immunocytochemistry study of isolated ventricular myocytes with a panel
of antibodies against KATP channel subunits concluded
that Kir6.x/SURx subunits do not localize to mitochondria (579). Moreover, mitochondrial function and mitochondrial KATP channel activity are unaffected in
Kir6.1⫺/⫺ or Kir6.2⫺/⫺ mice (595, 876), suggesting that
these subunits are not essential components of the mitochondrial channel. The current consensus appears, therefore, to be that these subunits do not comprise the mitochondrial KATP channel (718, 876, 920). Flavoprotein
oxidation elicited by diazoxide (measured as an increased
autofluorescence), however, is absent in ventricular myocytes from SUR2⫺/⫺ mice (901), suggesting a possible
role for SUR2. Indeed, low-molecular-weight SUR2 isoforms have been identified that may be components of the
mitochondrial KATP channel. When heterologously ex-
pressed, a 55 kDa SUR2 splice variant colocalizes with
mitoTracker dyes in COS1 cells (901). However, when
coexpressed with Kir6.x, patch-clamp methods demonstrate the presence of plasmalemmal KATP channels that
are blocked by millimolar ATP levels but are practically
insensitive to pinacidil, diazoxide, or glibenclamide (3).
Although this finding awaits confirmation, there is now a
report suggesting that ROMK2, a splice variant of
Kir1.1, may contribute to the molecular composition of
mitochondrial KATP channels (240) (for a detailed discussion, see sect. III).
3. Physiological roles of mitochondrial KATP
channels
The majority of observations concerning the function of
mitochondrial KATP channel are based on modulation of
mitochondrial function by K⫹ channel inhibitors and
openers. These indexes include changes in mitochondrial
matrix volume, mitochondrial potential, and oxygen
consumption (170, 171, 636). The primary function of
the mitochondrial KATP channel appears to be to allow
K⫹ transport into the mitochondrial matrix which, in
concert with the operation of a K⫹/H⫹ antiporter, may be
involved in mitochondrial volume homeostasis (257,
258). The resulting matrix swelling may improve the rate
of oxidative metabolism and the formation of reactive
oxygen species. The activity of the mitochondrial KATP
channel activity may also be coupled to the cellular energetic state via its inhibition by ATP and ADP (386). Nevertheless, the mitochondrial KATP channel appears to
have an important function under basal conditions,
which should become clearer when molecular approaches have been developed to study this channel.
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1
Data were derived from flux assays and not from direct evaluation of the channel function. 2ATP was effective
in inhibiting mitoKATP channel activities when added to the cis chamber. 3Channels with unitary conductances
of 18 or 100 pS were also observed, but not studied.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Table 5. Possible subunits of mitochondrial KATP channels
Subunits
Species
Kir6.1
Rat
Kir6.1
Rabbit
Kir6.1 and
SUR1
Kir6.1 and
Kir6.2
Preparation
Mitochondrial fractions
prepared from skeletal
muscle
Isolated cardiac myocytes
Result
Reference
Nos.
WB, ICC, EM
Single band at 51 kDa in WB
768
ICC
718
WB
Heterologously expressed Kir6.1 and Kir6.2 do
not localize to mitochondria. Also, no Kir6.1
mitochondrial localization in ICC using an antiKir6.1 antibody
Bands at 50 and 155 kDa, respectively
776
WB
Bands at 48 and 40 kDa, respectively
746
WB
Bands at ⬃50 kDa for both Kir6.x subunits.
SUR2 migrates at ⬃25 kDa
473
ICC
147
WB
Immunolocalization observed for all three
subunits
Strong expression of Kir6.1 (43 kDa) and weak
expression of Kir6.2 (48 kDa)
Unknown band sizes
WB and ICC
Neither subunit is present in mitochondria
837
WB
Band at ⬃50 kDa
113
WB
48 and 70 kDa bands, respectively
216
WB
Unknown band size
863
WB
None of these subunits is present in
mitochondrial membranes. Kir6.1 (43 kDa),
Kir6.2 (40 kDa), and SUR2A (150 kDa) were
present in microsomal membranes
Immunolocalization
468
Bands at 28, 55, and 68 kDa are expressed at
higher levels in mitochondrial membranes
compared with microsomal membranes
SUR2A (150 kDa) and SUR2B (50 kDa) are
present in mitochondria
GFP-ROMK2 is enriched in mitochondria
901
WB
Kir6.2
Rat
SUR2
Mouse
Isolated cardiac
ICC
mitochondria
Mitochondrial membranes WB
SUR2A and
SUR2B
Kir1.1
Rat
Mitochondrial membranes WB
Hamster
Mitochondrial membranes WB
from CHO cells
934
657
255
931
240
ICC, immunocytochemistry/immunofluorescence; EM, electron microscopy; WB, Western blot.
G. KATP Channels in Other Cell Types That
May Affect Cardiovascular Function
1. KATP channels regulate neurotransmitter release
from sympathetic nerves
A novel role for KATP channels has recently been described
in the sympathetic nervous system, where it was found that
norepinephrine (NE) release is inhibited by active KATP
channels (612). The data supporting this finding are that
KATP channel openers inhibit NE release as well as the increase in atrial rate induced by electrical stimulation of the
206
sympathetic ganglion (571, 612). In contrast, KATP channel
blockers had the opposite effects. Interestingly, NE release
(as well as changes in atrial rate by sympathetic nerve stimulation) were quite sensitive to diazoxide (571), which activates SUR1- or SUR2B-containing KATP channels much
more effectively than cardiac SUR2A-containg KATP channels (TABLE 3). However, the molecular nature of these
channels (as well as the signaling pathways responsible for
KATP channel-regulated exocytosis) still needs to be investigated. These channels were also highly sensitive to sulfonylureas, which raises potential issues for diabetes patients
treated with these compounds.
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PC12 cells Mitochondria-enriched
fractions
Rat
Mitochondrial membrane
proteins from
ventricular myocytes
Kir6.1, Kir6.2, Mouse and Mitochondrial membranes
and SUR2
rat
isolated from the heart
or liver
Kir6.1, Kir6.2, Rat
Isolated cardiac
and SUR2
mitochondria
Kir6.1
Rat
Mitochondrial membranes
isolated from the heart
Kir6.1 and
Rat
Mitochondrial membranes
Kir6.2
isolated from liver and
hippocampus
Kir6.2 and
Mouse
MIN6 beta cells
SUR1
Kir6.1
Rat
Mitochondrial membranes
isolated from the brain
Kir6.1 and
Mouse
Mitochondrial membranes
SUR1
isolated from the heart
Kir6.1
Rat
Mitochondrial membranes
from H9C2 cells
Kir6.1, Kir6.2, Rat
Microsomal (sarcolemmal)
and SUR2A
and mitochondrial
membranes
Technique
KATP CHANNELS IN CARDIOPROTECTION
2. KATP channels regulate acetylcholine release
VIII. CARDIOVASCULAR PHENOTYPES OF
GENETIC MOUSE MODELS FOR
STUDYING KATP CHANNELS
Gene targeting in mice has been useful to elucidate the physiological and pathophysiological functions of KATP channels. Knockout mouse models have been developed in
which expression of each of the KATP channel subunits has
been eliminated and some of the KATP channel subunits
have been transgenically overexpressed in a tissue-specific
manner.
A. Pore-Forming Subunits
1. Kir1.1
The Kcnj1 gene is located on mouse chromosome 9
(32,372,418 to 32,399,192) and has three exons. Targeted
disruption of exon 2 in mice leads to neonatal mortality,
with ⬃95% succumbing before 3 wk of age (523). The
surviving mice had severe kidney defects and are dehydrated with metabolic acidosis, dysregulated blood levels of
Na⫹ and Cl⫺, reduced blood pressure, polydipsia, polyuria,
and poor urinary concentrating ability. With careful breeding the survival rate can be improved, but kidney defects
remain (526). Heterozygous Kcnj1⫹/⫺ rats have a slightly
2. Kir6.1
In mice, the Kcnj8 gene resides on chromosome 6 at location 142,522,146 to 142,528,581 and it contains three exons. The coding region of Kir6.1 is contained in exons 2 and
3. In the Kir6.1⫺/⫺ mouse, the strategy was to delete the
coding region of exon 3 (565). Phenotypically, these mice
develop vascular problems. They lack vascular KATP channels and develop coronary artery vasospasms that resemble
Prinzmetal (or variant) angina in humans (565). Conditional knockout mice that lack Kir6.1 specifically in smooth
muscle cells are hypertensive, and the vascular smooth muscle cells fail to respond to vasodilators (35), underscoring
the important role of Kir6.1 in blood flow control. Hypotension was also noted in mice with transgenic expression of
Kir6.1 gain-of-function subunits in vascular smooth muscle
(492). Despite the significance of these findings, the
Kir6.1⫺/⫺ mice or vascular Kir6.1 overexpression approaches have not been employed to investigate its role of
blood flow in pathophysiological conditions, such as in the
context of cardiac ischemia, reperfusion, ischemic preconditioning, and the no-reflow phenomenon, where maintaining adequate blood flow is expected to beneficial. Transgenic expression of dominant-negative, pore-mutant,
Kir6.1 subunits in the endothelium has revealed a role for
KATP channels in the release of endothelin-1 from the endothelium (536). The release of endothelin-1 from the hearts
of these mice was elevated compared with wild-type littermates, which was associated with an increased coronary
resistance. Pretreatment of mice with bosentan (a blocker of
ET-1 receptors) restored the elevated coronary resistance.
This finding suggests that opening of endothelial KATP
channels is associated with suppression of ET-1 release
through cellular mechanisms that are yet to be determined.
It should be noted that the latter result does not imply an
exclusive role for Kir6.1 in the endothelium since the mutant subunits may heteromultimerize with endogenous
Kir6.2 to eliminate KATP channel function (810, 907).
3. Kir6.2
The Kcnj11 gene (encoding the Kir6.2 subunit) is located
on mouse chromosome 25 (position 19,105,218 to
19,106,363). It is intronless and contains the entire coding
region, which has been targeted for deletion (564). Since
Kir6.2 forms a component of the pancreatic ␤-cell KATP
channel, which triggers insulin release, one would expect
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Acetylcholine (ACh) is synthesized and released in the central nervous system as well as from autonomic ganglia in the
peripheral nervous system and in postganglionic parasympathetic neurons. In the heart, vagal nerve stimulation
causes ACh release, which slows the heart rate by G protein-mediated activation of Kir3.x channels. It was found
that ACh release evoked by electrical stimulation of isolated
guinea pig atria was stimulated by KATP channel blockers,
suggesting a role for negative feedback of KATP channels in
exocytotic processes in these neurons (435). Interestingly,
ACh release by neurons in the ileum is affected similarly by
KATP channel activity (942), whereas mesenteric neurons
are not affected by KATP channel modulation (714, 942).
These findings suggest diversity of function and/or pharmacology of KATP channels in various neuronal compartments,
which remains to be studied. The KATP channels in dorsal
vagal neurons may be composed of Kir6.2/SUR1 subunits
(425) (as in the pancreas; TABLE 2), which again raises issues of potential cardiovascular side effects of sulfonylurea
treatment in the setting of diabetes. The study of the molecular composition of the channels in these neurons, the molecular mechanisms responsible for coupling KATP channel
activity to exocytotic release, and the pathophysiological
consequences of these findings await more refined tools
(such as mice lacking KATP channels in specific tissue compartments).
lower (2–5 mmHg) blood pressure than wild-type littermates, and a substantially lower blood pressure when on a
high-salt diet (935). The latter study demonstrated an important role for the ROMK channels to maintain kidney
function and revealed a critical role of ROMK channels in
blood pressure regulation. No other cardiovascular phenotypes (or mitochondrial defects) have so far been reported
for Kcnj1⫺/⫺ animals.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
these mice to be diabetic. However, the Kir6.2⫺/⫺ mice
largely lack the expected hyperglycemic phenotype, but
have been used to demonstrate that Kir6.2 is a key regulator
of glucose- and sulfonylurea-induced insulin secretion
(720).
208
B. Accessory Subunits
1. SUR1
The SUR1 subunit contains 17 transmembrane segments
and is encoded by the Abcc8 gene on the mouse chromosome 25 (at location 19,072,876 to 19,091,318). Abcc8 is
comprised of multiple exons, and transcriptional activity
can give rise to several SUR1 splice variants (289, 323, 330,
685, 704). Two groups have produced SUR1⫺/⫺ mice by
either deleting exon 1, containing promoter regions and the
starting methionine (732), or exon 2 (717). Although neither mouse model displayed the expected severe dysregulation of insulin release, they have been useful in helping us to
understand how insulin release is fine-tuned (5). SUR1 also
has other functions, but reports demonstrating a role in the
cardiovascular system are only now emerging. For example,
the SUR1⫺/⫺ mice were instrumental in the identification of
a novel subtype of SUR1-based, diazoxide-sensitive, KATP
channels in mouse atria (237), which may also be present in
the human atria and ventricle (222). The SUR1-null mice
are unexpectedly protected from cardiac ischemia; they exhibit a reduced postischemic infarct size and preservation of
left ventricular function upon reperfusion after ischemia
(207). Interestingly, the spread of the hemorrhagic contusion and capillary fragmentation in spinal cord injury are
also prevented in SUR⫺/⫺ mice (745). These results therefore suggest a detrimental role for SUR1 during stress conditions. It should be noted that SUR1 effects may not originate in the cardiovascular system itself, but it may affect
the sequelae of ischemia/reperfusion through potential actions on other cell and tissue types (487).
2. SUR2
The SUR2 subunit is coded by the Abcc9 gene on mouse
chromosome 6 (position 142,546,356 to 142,659,537) and
has 40 exons (2 of which are untranslated). Several splice
variants have been identified (114, 164, 727, 901). The two
“full-length” splice variants that are most commonly studied, SUR2A and SUR2B, differ from each other by alternative use of exons 39 and 40. SUR2⫺/⫺ mice have been generated in which two exons were targeted to remove regions
in the first of the two intracellular nucleotide binding folds
that are involved in ATP/ADP binding (116). Similar to the
Kir6.1⫺/⫺ mice, these mice are hypertensive and exhibit
spontaneous coronary vasospasms (115). The SUR2⫺/⫺
mice are paradoxically protected against ischemia (762).
The protection may be due to spontaneous coronary vasospasms that occur in the SUR2⫺/⫺ mouse hearts that may
cause short bursts of ischemia (similar to ischemic preconditioning). Restoring SUR2 specifically in the heart by
transgenic expression within the SUR2-null background led
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Mice with cardiac-specific transgenic overexpression of Kir6.2
gain-of-function mutant subunits (Kir6.2-⌬N30,K185Q) exhibited no gross physiological or morphological phenotypes
(235, 458). Interestingly, however, although the ATP
sensitivity of the KATP channels was decreased in excised
patches, channels remained closed in the intact cell. A
similar observation was made with cardiac-specific expression of a Kir6.2 subunit carrying a mutation associated with neonatal diabetes (Kir6.2-V59M mutant),
which led to channels with altered ATP sensitivity, but no
cardiac abnormalities (120). Transgenic overexpression of
SUR1 and gain-of-function Kir6.2 (⌬N30, K185Q) subunits in the ventricle results in embryonic lethality (807),
but the physiological relevance of this overexpression study
is not clear. Knockout approaches have also been used. The
Kir6.2⫺/⫺ mice, which lack ventricular KATP channels, have
no overt obvious cardiac defects (720). Closer inspection
has revealed important physiological roles for KATP channels in the cardiovascular system. The first demonstration
was that the Kir6.2⫺/⫺ mice had an impaired tolerance to
exercise and stress (940). The fact that it was the ventricular
KATP channel (and not the loss of KATP channels in another
somatic compartment) that was responsible for this deficit
was underscored by the use of transgenic mice with cardiacspecific overexpression of dominant-negative Kir6 subunits, which likewise had an impaired exercise tolerance
(536). Kir6.2⫺/⫺ mice also develop arrhythmias and sudden
death with sympathetic challenge (likely due to cellular
Ca2⫹ overload since it is preventable by Ca2⫹ channel
blockers), which points to a vital protective function of
KATP channels under physiological conditions (940). A recent finding points to a more subtle and important physiological function: when the heart rate is elevated, the action
potential duration adapts (decreases) over the time course
of a few minutes (202), which is responsible for a decreased
refractoriness and prevention of arrhythmias. Both glibenclamide and loss of KATP channel function (achieved by
cardiac-specific overexpression of dominant-negative Kir6
subunits) largely eliminates frequency adaptation, which
points to a key physiological action of KATP channels in
action potential adaptation at elevated heart rates (941).
Moreover, exercise led to upregulation of ventricular KATP
channel subunit expression as well as a more robust KATP
channel-dependent heart rate adaptation in mice (941). The
Kir6.2⫺/⫺ mouse model is useful to study sarcolemmal
KATP channels, since ventricular KATP channels are absent
in the mice, whereas mitochondria KATP channel function is
preserved (771). Indeed, they have helped to elucidate important roles for KATP channels during pathological pro-
cesses such as ischemia and ischemic preconditioning (see
sect. IX).
KATP CHANNELS IN CARDIOPROTECTION
IX. PATHOPHYSIOLOGICAL ROLES OF KATP
CHANNELS
Some of the physiological roles of cardiovascular KATP
channels have been highlighted in the section VII and include functions such as the frequency adaptation of the
ventricular action potential duration, the release of atrial
natriuretic peptide from the atria, vasodilation and increased blood flow in smooth muscle, release of vasoactive
substances from the endothelium, and mitochondrial matrix volume regulation. It is conceivable that any of these
functions may impact cardiovascular pathophysiology, but
few of these have been studied in detail. In this section we
deal mainly with stress responses and the consequences of
coronary artery disease.
A. Cardiac KATP Channels Protect Against
Stress
Mice with somatic deficiency of Kir6.2 subunits or with
transgenic, cardiac-specific overexpression of dominant
negative Kir6 subunits have a phenotype of impaired stress
responses and intolerance to an exercise load (described in
sect. VIII). Cellular mechanisms are likely to relate (at least
in part) to the prevention of intracellular Ca2⫹ overload
(FIGURE 12). Indeed, upon catecholamine challenge, ventricular myocytes isolated from the hearts of Kir6.2⫺/⫺ mice
exhibit defective action potential shortening, which predisposes the myocardium to early afterdepolarizations and arrhythmias (510). In further support, metabolic inhibition
with the mitochondrial uncoupler DNP leads to Ca2⫹ overload in COS-7 cells, which is mitigated when cells are
transfected with Kir6.2/SUR2A cDNAs (408). There is in
vivo evidence for a central role of KATP channels in protecting the myocardium against Ca2⫹ overload: using
manganese-enhanced cardiac magnetic resonance imaging, myocardial Ca2⫹ accumulation was exacerbated and
myocardial function was impaired in hearts of Kir6.2⫺/⫺
Ca2+
KATP channel
APD shortening
Ca2+
Inotoropy
ATP use
Energy
sparing
mKATP channel
Mitochondrial
damage
Volume regulation
ATP production
ROS
Cardiomyocycte
FIGURE 12. Possible mechanisms by which opening of KATP channels may protect against stress responses. Stress-induced opening
of the sarcolemmal type of KATP channels may cause action potential
duration shortening or accelerate action potential duration shortening during metabolic stress. The shorter action potential may limit
Ca2⫹ entry from extracellular sources and may limit Ca2⫹ overload,
which in turn may preserve mitochondrial integrity. The lower cytosolic Ca2⫹ may also cause a negative inotropic effect, which in turn
will limit the energy being used by the cardiomyocyte, resulting in an
ATP-sparing effect. The mitochondrial subtype of KATP channels may
directly preserve mitochondrial function through effects in membrane potential and matric volume regulation, enhancing ATP synthesis. Production of reactive oxygen species (ROS) may further
serve as a trigger response for preservation mechanisms.
mice (305). Cardiac overexpression of ATP-insensitive
Kir6.2 mutant subunits also results in defects in intracellular Ca2⫹ handling (655). In addition to the effects on
intracellular Ca2⫹, KATP channels may additionally protect against stress by preserving mitochondrial function.
In rat ventricular myocytes, for example, shRNA knockdown of Kir6.2 (by 50%) not only leads to disrupted
intracellular Ca2⫹ homeostasis, but also to oscillations of
mitochondrial membrane potential (764). Mitochondrial
KATP channels may of course also directly participate in the
protection against stress (259). Targeted expression of Kir6.2
in the mitochondria of HEK293 and HL-1 cells confers protection against hypoxic stress (516). Although the role of
Kir6.2 in mitochondria is questionable (see TABLE 5), this
study provides good nonpharmacological evidence that increased K⫹ fluxes in mitochondria may participate in protection against stress. Finally, KATP channels may facilitate the
cardiac response to stress by regulating PGC-1␣ and its target
genes, in part through the FOXO1 pathway (366).
B. Myocardial Ischemia and Reperfusion
The leading cause of heart disease and heart failure is a
deficit of coronary blood flow due to atherosclerosis and
thrombosis. The reader is referred to reviews and books for
full details on this subject (94, 204, 243, 339, 396, 397,
623, 630). In short, myocardial ischemia occurs when
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to further protection against ischemia-induced infarct development and improved postischemic contractile recovery
(763). Another study also demonstrated that nonspecific
transgenic overexpression of SUR2A in mice (driven by the
CMV promoter) is protective against ischemia and that the
hearts from these mice had reduced infarct sizes in response
to ischemia-reperfusion compared with wild-type (189).
The interpretation of the data with the SUR2⫺/⫺ mice is
complicated due to the presence of remaining short-form
SUR2 isoforms (727). A different knockout design (deleting
exon 5) that eliminates all SUR2 isoforms has recently been
described. Homozygous exon 5 deletion (SUR2-Ex5) results in
neonatal mortality with progressive cardiac dysfunction in the
first weeks of life (212). At present it is unclear why SUR2
knockout results in such a severe phenotype, whereas Kir6.2
knockout mice have milder cardiovascular defects.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
1. K⫹ efflux from ischemic tissue: do KATP channels
contribute?
The loss of K⫹ ions from the ischemic myocardium is an
early response and starts to occur within seconds after the
interruption of oxygenated blood flow (328, 351, 445). Due
to flow restriction, K⫹ accumulates in the extracellular
space, which in turn causes membrane depolarization, action potential shortening, and a decreased rate of rise of the
action potential (which is an important determinant of
rapid electrical conduction). Initially, the hypothesis was
raised that K⫹ efflux occurs as a result of an ionic shift that
occurs in response to electrogenic anion loss from ischemic
cells in the form of lactate (137, 443). The finding that
hypoxia and metabolic inhibition result in an increase of a
specific K⫹ conductance associated with 42K⫹ efflux (379,
847, 850), coupled with the description of the KATP channel
(607, 815), led to studies to investigate the role of this
channel during the initial phase of K⫹ efflux. In the earliest
studies performed with isolated rat, guinea pig, and rabbit
hearts rendered globally ischemic by stop-flow or low flow,
glibenclamide (1–10 ␮M) was found to strongly attenuate
extracellular K⫹ accumulation during ischemia (424, 871).
Moreover, there was no correlation between early lactate
and K⫹ efflux rates (424), and glibenclamide had no effect
on the extracellular acidification (871). Using a variety of
experimental preparations, others have also reported glibenclamide, more so than tolbutamide, to inhibit K⫹ or Rb⫹
loss during simulated myocardial ischemia (399, 835, 866,
870). The KATP channel blocker 5-hydroxydecanoate also
inhibits K⫹ release from the ischemic rat (600) or guinea pig
(681) myocardium. Thus KATP channels appear to have a
role in K⫹ loss early during cardiac ischemia. It should be
noted, however, that glibenclamide only partially prevents
210
K⫹ accumulation and is only effective during the early (⬃10
min) phase of ischemia (424, 871). Moreover, genetic deficiency of KATP channels (experiments with Kir6.2⫺/⫺ mice)
does not prevent K⫹ accumulation during ischemia (680).
Therefore, in addition to KATP channels, other mechanisms
contribute to K⫹ accumulation in the ischemic myocardium, including shrinkage of the extracellular space, diminished K⫹ reuptake due to Na⫹/K⫹ pump inhibition, and K⫹
loss through other pathways, such as inward rectifier K⫹
channels, Na⫹-activated K⫹ channels, arachidonic acid-activated K⫹ channels, and other mechanisms (273, 670, 800,
870). It is also possible that K⫹ loss occurs as a charge
balance mechanism to compensate for Na⫹ influx that occurs during ischemia. Indeed, in the presence of blockers of
Na⫹ influx pathways (Na⫹ channels, L-type Ca2⫹ channels,
Na⫹-K⫹-2Cl⫺ cotransport, and the Na⫹-H⫹ exchange), tissue K⫹ accumulation in response to ischemia is completely
prevented in an arterially perfused rabbit interventricular
septum preparation (733). In this paradigm, Na⫹ influx
into ischemic cells is the major driver, and the KATP channel
(along with other K⫹ permeation pathways) acts merely as
a flux coupling pathway to maintain electroneutrality in the
ischemic tissue. This mechanism may also explain why
KATP channel openers (such as cromakalim) do not lead to
K⫹ accumulation in normoxic tissue, why KATP channel
blockers only partially prevent K⫹ accumulation, and why
in some studies (but see Ref. 569) KATP channel openers
(such as cromakalim) fail to enhance K⫹ loss during ischemia (424, 733, 843).
2. Role of KATP channels during action potential
shortening that occurs during acute ischemia
Action potential shortening occurs during hypoxia and
metabolic inhibition. KATP channel opening is involved
since it can be prevented by glibenclamide (177) or genetic knockout of Kir6.2 subunits (270). Following coronary artery occlusion, action potential duration shortening also occurs (associated with diastolic membrane
potential depolarization) (392, 445, 483), but the role of
the KATP channel may be quite different since the APD
shortening during ischemia happens for different reasons
(due to K⫹ accumulation in the restricted extracellular
spaces caused by inadequate blood flow and washout; see
above). Indeed, action potential duration shortening occurs with the same time course as extracellular K⫹ accumulation, starting within 10 –30 s of coronary occlusion
and progressing over the next 10 –15 min (445) and then
stabilizes to some extent (615). Moreover, in dog heart,
infusing K⫹ to raise the extracellular K⫹ from 3.4 to 5.9
mM causes action potential shortening similar to that
observed with ischemia, and superimposed hypoxia does
not lead to significant additional shortening (183). Conduction slowing, in contrast, cannot solely be explained
by raising the extracellular K⫹ (183, 446), and conduction paradoxically even accelerates transiently during the
first minute of ischemia due to the elevated extracellular
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blood and oxygen supply do not meet myocardial demand.
The lack of oxygen and nutrients supply and the accumulation of metabolic waste products result in a progressive
succession of events that starts with immediate biochemical
and functional abnormalities, including metabolic impairment, rapid K⫹ loss from myocytes within the ischemic
zone, and extracellular K⫹ accumulation. Loss of myocardial contractility occurs within 60 s and other changes that
take a more protracted time course. Reperfusion (restoration of blood flow) can occur, but loss of viability (irreversible injury) occurs within 20 – 40 min following total occlusion of blood flow. The loss of contractility and the development of lethal arrhythmias are responsible for the
majority of sudden death events. As summarized below,
KATP channels appear to have a role in many of these processes [also refer to other reviews (69, 236, 293, 295, 338,
611, 622)]. Cardiac ischemia is a complex event, and the
effects of KATP channel opening are more complex. Overall,
KATP channel opening can be both detrimental (e.g., by
precipitating arrhythmias and maintaining ventricular fibrillation) and protective (e.g., by limiting he development
of a post-ischemic infarct).
KATP CHANNELS IN CARDIOPROTECTION
3. Reasons for KATP channel open during ischemia
The question appears therefore not to be whether KATP
channels open during ischemia, but what the reasons are for
their opening, considering that ATP needs to decrease to
submillimolar levels for them to open (at least in patchclamp experiments) (124). This finding appears inconsistent with the rapid CrP depletion, but slower decline in
tissue ATP levels that occurs during myocardial ischemia
(211, 465, 574). Experimental data demonstrate that a
poor relationship exists between cellular ATP levels and
KATP channel opening. For example, during metabolic
blockade of ferret hearts, severe action potential shortening
occurs (44% after 5 min) at a time when there were no
major changes in the tissue ATP concentration (it decreased
from 5.4 to 4.3 mM) (206). Subsequent addition of glucose
led to a 70% recovery of APD with only a 10% increase in
ATP concentration. Also, in voltage-clamped rabbit papillary muscles, KATP channel-dependent APD shortening occurs during hypoxia, despite only a modest (⬃25%) decline
in tissue ATP content (177). A contributing factor might be
the sharp and rapid decline in the calculated free energy of
ATP hydrolysis during the first few minutes of ischemia
(233). Other factors occurring during ischemia, such as cellular acidosis, changes in inorganic phosphate, adenosine
production, and changes in phospholipid content may act
to lower the channel=s ATP sensitivity and/or to promote its
opening (124). For example, the KATP channel is activated
by AMPK (767, 905), the guardian of cardiac energy status
(325), and by adenylate kinase phosphotransfer reactions
(100), as a result of small changes in intracellular AMP,
which occurs rapidly. In dog heart, for example, the AMP/
ATP ratio doubles within just 1 min of regional ischemia,
mainly due to an increase in the AMP levels (621). Other
factors may further contribute to KATP channel opening.
For example, due to their high surface density and large
unitary conductance, significant electrophysiological alterations are possible when only a small percentage of the
KATP channels open (232, 726). There may also be intracellular factors that remain to be identified that may modulate
KATP channel opening (786). Finally, it may not be the total
cellular ATP/ADP levels that regulate KATP channels, but
rather the levels in the immediate microenvironment of the
channel. Indeed, O2 and ATP gradients are known to occur
inside cells (407). The local ATP level at the channel will be
determined by the site and rate of ATP production, the rate
of ATP diffusion, and the rate of ATP consumption. The
source of ATP may be more important than cellular content
as a cause of intracellular ATP compartmentalization (624).
In this regard, KATP channels are preferentially regulated by
glycolysis (178, 179, 866) and directly associate with glycolytic enzymes (141, 179, 358, 409, 433), which lends
credence to the idea that KATP channel activity is regulated
locally by compartmentalized changes in nucleotide concentrations.
4. Role of KATP channels in arrhythmias that occur
during ischemia and reperfusion
Ventricular arrhythmias can occur early (first 10 min) during ischemia (phase 1a arrhythmias), or the occurrence can
be delayed. The phase 1b arrhythmias occur between 15
and 60 min after the onset of ischemia, and phase 2 arrhythmias occur even later (after ⬃90 min) (394). Serious arrhythmias can also ensue upon reperfusion of the ischemic
tissue. Distinct mechanisms underlie these types of arrhythmias (123, 444, 484, 676), and KATP channel opening may not
necessarily affect these types of arrhythmias in the same way (if
at all).
A) INITIATION OF ARRHYTHMIAS EARLY DURING CARDIAC ISCHEMIA.
Early during ischemia, the membrane potential depolarizes
and action potential shortening occurs, but only within the
ischemic zone (due to extracellular K⫹ accumulation; see
above). A key role for K⫹ is illustrated by the finding that an
increased K⫹ concentration in the perfusate (to balance the
K⫹ gradients) prevents arrhythmias during early ischemia
(but not during reperfusion) in isolated rat hearts (527,
679). Since the electrophysiological changes are regional,
gradients are established between the ischemic and the nonischemic zones, thus creating an electrical border zone in
which arrhythmias can ensue (95, 205, 391). During this
early stage, electrical gradients and dispersed refractoriness,
together with slowing of conduction, contribute to the formation and maintenance of the ischemic arrhythmias (329,
446, 865). Arrhythmias can be triggered by extrasystoles
(“triggered activity”) or by abnormal automaticity. The
“trigger” may take the form of an afterdepolarization occurring during the action potential (“early afterpotentials”)
or during diastole between action potentials (“late afterpotentials”). Given this complex set of events, it is difficult to
predict how KATP channel opening may affect the outcome.
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K⫹ levels (205, 243). Intrinsic changes in ionic currents
also contribute to the action potential changes. Experimental data and modeling studies support a role for a
decreased Na⫹ current as being responsible for conduction slowing (99, 726) with an additional role for the
L-type Ca2⫹ current in action potential shortening (438).
KATP channel activation may also contribute to APD
shortening. However, since KATP channels contribute
only partially to extracellular K⫹ accumulation during
ischemia, which is the major determinant of action potential shortening and membrane depolarization, modulators of KATP channels are expected to only have partial
effects. Indeed, blocking KATP channels with glibenclamide or 5-hydroxydecanoate slows (but does not prevent) action potential shortening during ischemia in a
variety of experimental models and in different species
(TABLE 6). Moreover, most studies found that KATP channel openers, including levcromakalim, pinacidil, HMR1098, and diazoxide, accelerate the ischemia-induced action potential shortening (TABLE 6), at least within the
first 10 –15 min before a plateau is reached (615).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Table 6. Effects of KATP channel modulation on the action potential duration of metabolically impaired cardiac myocytes
Species
Preparation
Compound
Guinea
pig
Isolated right ventricular Glibenclamide (1–3 ␮M)
muscle
Guinea
pig
Papillary muscle
Guinea
pig
Intervention
Result
Reference
Nos.
Attenuates the hypoxia-induced
decreased APD
400
Glibenclamide (10 ␮M)
Hypoxia or simulated
ischemia
Attenuates the decreased APD
during hypoxia
533,
862,
871
Papillary muscle
Glibenclamide (20 ␮M)
Hypoxic, glucose-free
solution or DNP (10
␮M), glucose-free
solution
Glibenclamide partially inhibited the
action potential shortening during
hypoxia or metabolic inhibition
588
Guinea
pig
Papillary muscle
Glibenclamide (10–200 ␮M)
Oil-immersion ischemia
or simulated ischemia
Glibenclamide prevented or slowed
action potential shortening during
simulated ischemia1
265, 835
Guinea
pig
Isolated ventricular
myocytes
Glibenclamide (1 ␮M)
Hypoxia
Glibenclamide attenuated the
decreased APD during hypoxia
783
Guinea
pig
Isolated ventricular
myocytes
Glibenclamide (1 ␮M)
Levcromakalim (3–30
␮M)
Glibenclamide had no effect on the
APD, but significantly reduced
APD shortening induced by
levcromakalim
400
Guinea
pig
Right ventricular free
wall
Glibenclamide (1–30 ␮M)
Simulated ischemia
Glibenclamide attenuated action
potential shortening during
simulated ischemia
633,
639,
729
Guinea
pig
Arterially perfused right
ventricular wall
Glibenclamide (1 or 10 ␮M)
No-flow ischemia
Glibenclamide attenuates the action
potential shortening during
ischemia
132, 133
Guinea
pig
Isolated, Langendorffperfused heart
Glibenclamide (ED50 95 nM)
HMR-1098 (ED50 550 nM
Low-flow ischemia
Ischemia-induced AP shortening was
inhibited by glibenclamide
867
Guinea
pig
Isolated, Langendorffperfused heart
Glibenclamide (10 ␮M)
Global ischemia
Ischemia causes electrical
inhomogeneity (the APD shortens
more in the left than in the right
ventricle). Glibenclamide prevents
LV APD shortening
629
Dog
Anesthetized open-chest 5-Hydroxydecanoate (30 mg/
model
kg) or glibenclamide (0.15
or 0.3 mg/kg iv)
Regional ischemia
Suppress or abolish the occlusioninduced shortening of monophasic
APD90
311, 577
Dog
Anesthetized open-chest Glibenclamide (0.3 mg/kg iv)
model
Regional ischemia
Glibenclamide prevented the
reduction of the monophasic APD,
particularly during the first
occlusion period, and it worsened
post-ischemic dysfunction
897
Dog
Anesthetized open-chest Glibenclamide (0.3 mg/kg)
model
Regional ischemia
The extent of ST segment elevation
during coronary occlusion was
attenuated by glibenclamide
466
Dog
Arterially perfused
myocardium
Global ischemia
Glibenclamide partially inhibited the
action potential shortening during
ischemia
588
Dog
Anesthetized open-chest Intracoronary cromakalim (1
model
␮g·kg⫺1·min⫺1)
Regional ischemia
During coronary occlusion,
cromakalim significantly reduced
APD95 compared with the vehicle
group
149
Pig
Anesthetized open-chest Glibenclamide (0.5 mg/kg,
model
followed by 50 ␮g/min iv)
Regional ischemia
Abolish the reduction in the
epicardial MAP50 during ischemia
706
Pig
Anesthetized open-chest HMR-1883 (3 mg/kg iv)
model
Regional ischemia
HMR 1883 reduced monophasic
action potential shortening during
coronary ischemia
874
Pig
Anesthetized open-chest Cromakalim (0.3 mg/kg) or
model
pinacidil (3 mg/kg)
Regional ischemia
During ischemia, cromakalim or
pinacidil caused a greater
reduction in APD90
150
Sheep
Anesthetized open-chest Glibenclamide (0.4 mg/kg)
model
Regional ischemia
Glibenclamide prevented the
monophasic action potential
shortening during ischemia
480
Cat
Isolated left ventricular
myocytes
Metabolic inhibition with
cyanide (1 mM)
The AP shortening during cyanide
treatment was partially reversed
249
Rabbit
Anesthetized open-chest Glibenclamide (0.3–3 mg/kg
model
iv)
Regional ischemia
Glibenclamide had no effect on
baseline monophasic APD, but
attenuated action potential
shortening during ischemia1
747
Glibenclamide (20 ␮M)
Glibenclamide (0.3 ␮M)
Continued
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Hypoxia
KATP CHANNELS IN CARDIOPROTECTION
Table 6.—Continued
Species
Preparation
Compound
Intervention
Result
Reference
Nos.
Rabbit
Isolated, arterially
perfused
interventricular
septum
Glibenclamide (1 or 100 ␮M)
Global ischemia
Glibenclamide attenuated the
shortening of APD induced by
global ischemia
347, 842
Rabbit
Isolated, arterially
perfused
interventricular
septum
Cromakalim (5 ␮M)
Global ischemia
Pretreatment with cromakalim led to
more rapid shortening of the APD
during ischemia
843
Rabbit
Blood-perfused papillary
muscle
Glibenclamide (5 ␮M)
Hypoxia or no-flow
ischemia
APD shortening was modest with
hypoxia and glibenclamide had no
effect on APD shortening2
892
Rabbit
Isolated, Langendorffperfused heart
Glibenclamide (30 ␮M)
Hypoxia
Glibenclamide partially prevented
165
APD shortening induced by hypoxia
Rabbit
Voltage-clamped
papillary muscle
Glibenclamide (10 ␮M)
Hypoxia
Glibenclamide attenuated the
decreased APD during hypoxia
Rabbit
Isolated, blood-perfused
papillary muscle
Glibenclamide (20 ␮M)
Ischemia with or without APD shortening during index
IPC
ischemia was more pronounced
with IPC. This decrease in APD
was blocked by glibenclamide
Rabbit
Anesthetized open-chest Glibenclamide (0.3–24 mg/kg Regional ischemia
model
iv)
Glibenclamide attenuated the rate of
APD shortening during ischemia
with an ED50 13 ⫾0.8 mg/kg3
51
Rabbit
Anesthetized animals
Glibenclamide (0.3 mg/kg ip)
or 5-HD (5 mg/kg iv)
Regional ischemia
Both glibenclamide and 5-HD
significantly suppressed ischemiainduced epicardial APD shortening
65
Rabbit
Isolated, Langendorffperfused heart
Diazoxide (50 ␮M)
Regional ischemia
No effect on the monophasic action
potential duration at the 15 min
time point after the onset of
ischemia
586
Rabbit
Isolated, Langendorffperfused heart
Pinacidil (10 ␮M) or diazoxide
(100 ␮M)
Global ischemia
Both compounds accelerated
794
ischemia-induced shortening of the
activation recovery interval (an
index of the action potential
duration)
Rabbit
Isolated, Langendorffperfused heart
Diazoxide (50 ␮M)
Regional ischemia
followed by
reperfusion
Both IPC and diazoxide significantly
prolonged APD and preserved
diastolic function at 60 min of
reperfusion compared to control
360
Rat
Isolated, Langendorffperfused heart
Cromakalim (10 ␮M) or
diazoxide (30 ␮M)
Global ischemia
Both compounds accelerated action
potential shortening during
ischemia. The effect of diazoxide
was only significant in the first 6
min of ischemia
262
Rat
Isolated, Langendorffperfused heart
5-Hydroxydecanoate (100
␮M)
Regional ischemia
5-Hydroxydecanoate prevented APD
shortening during ischemia
42
Ferret
Papillary muscle
Glibenclamide (0.2–10 ␮M)
Hypoxia
Glibenclamide prevented the action
potential shortening produced by
hypoxia
689
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787
APD, action potential duration; IPC, ischemic preconditioning. 1The same study described that in dogs, the
monophasic action potential duration did not shorten during ischemia in the no-drug group, but tended to
increase in the glibenclamide group (0.5 mg/kg iv) both before and during ischemia. 2Ischemia caused a more
severe APD shortening than hypoxia. Effects of glibenclamide on ischemia-induced APD are not reported. 3The
effective dose for a 50% maximal effect (ED50) was 13⫾0.8 mg/kg (n ⫽ 28). Despite the suppression in the
rate of APD shortening, there was no effect on the final magnitude of MAP shortening.
In general, triggered activity and automaticity are promoted
by interventions that oppose repolarization or hyperpolarization, such as an increased inward current or a decreased
outward current. Conversely, larger outward currents (such
as when KATP channels open) should mitigate these arrhythmogenic triggers. An argument could therefore be made
that KATP channel opening may be anti-arrhythmic since the
outward current generated will oppose these arrhythmogenic triggers. Indeed, in cellular assays, KATP channel
openers inhibit experimentally induced abnormal automaticity (481, 505, 753), or triggered arrhythmias elicited by
early afterpotentials (234, 753) or late afterpotentials (481,
505, 753). A counter argument, however, is that KATP channel opening may be pro-arrhythmic (at least to some extent)
since they contribute partially to the primary defect, which
is the loss of K⫹ from ischemic cells and K⫹ accumulation in
the ischemic zone. Both of these arguments probably hold
elements of the truth, given the spectrum of experimental
outcomes when studying the effects of KATP channel openers and blockers on arrhythmias during ischemia (TABLE 7).
On balance, it appears that KATP channel opening is detrimental during ischemia by causing arrhythmias. KATP chan-
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213
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Table 7. Effects of KATP channel openers and blockers on arrhythmias during ischemia and reperfusion
Species
Preparation
Intervention
Compound
Result
Reference
Nos.
Isolated,
Langendorffperfused hearts
Global ischemia,
followed by
reperfusion
Diazoxide (50 ␮M)
Diazoxide decreased the
incidence of reperfusioninduced arrhythmias
337
Rat
Anesthetized animals
Coronary artery
ligation (6
min), followed
by
reperfusion
HMR 1098 (3 mg/kg) or
diazoxide (10 mg/kg) or
pinacidil (0.1 mg/kg)
Decreased reperfusion
arrhythmia score by each
of the three compounds
276
Rat
Isolated,
Langendorffperfused hearts
Low-flow
ischemia
Cromakalim (10 ␮M),
pinacidil (30 ␮M),
glibenclamide (1 ␮M), or
tolbutamide (1 mM)
The KATP channel blockers
prevented ischemia-induced
VF, whereas the KCOs
increased VF incidence
880
Rat
Isolated,
Langendorffperfused hearts
Regional or lowflow ischemia
Glibenclamide (1 or 3 ␮M)
Glibenclamide exhibited potent
antifibrillatory activity,
abolishing irreversible VF
424
Rat
Isolated,
Langendorffperfused hearts
Global ischemia
Glibenclamide (1 ␮M),
cromakalim (10 ␮M) or
pinacidil (30 ␮M)
Glibenclamide had an
antifibrillatory effect,
whereas VF occurred faster
in the presence of KCOs
880
Rat
Isolated,
Langendorffperfused hearts
Regional
ischemia
followed by
reperfusion
Glibenclamide (1 or 10 ␮M)
Glibenclamide did not reduce
the incidence of
reperfusion-induced VF, but
had a defibrillatory action by
reducing the duration of VF
84
Rat and
dog
In vivo
Regional
ischemia
5-Hydroxydecanoate (200
mg/kg in rats or 3–10
mg/kg iv in dogs)
5-HD suppressed the
incidence of VF in rats and
improved VF threshold in
dogs
600
Rat
Isolated,
Langendorffperfused hearts
Regional
ischemia
Glibenclamide (10 ␮M) or
the KCO RP 49356
(10 ␮M)
Glibenclamide had
defibrillatory activity by
decreasing the incidence of
sustained VF. RP 49356
had no effect on ischemiainduced arrhythmias
658
Rat
In vivo
Regional
ischemia
HMR 1883 (1–10 mg/
kg iv)
HMR 1883 decreased the
incidence of VF during 30
min of coronary occlusion
873
Rat
Unanesthetized rats
Regional
ischemia by
coronary
artery ligation
Glibenclamide (5 mg/kg) or
pinacidil (0.03–1 mg/kg)
Both glibenclamide and
pinacidil decreased the VF
incidence within 15 min of
CAL and improved survival
490
Rat
Isolated,
Langendorffperfused hearts
Global ischemia,
followed by
reperfusion
Diazoxide (400 ␮M),
glibenclamide (50 ␮M) or
5-hydroxydecanoate
(1 mM)
Diazoxide increased the
incidence of reperfusioninduced arrhythmias,
whereas these arrhythmias
were decreased by
glibenclamide and 5-HD
431
Rat
Isolated,
Langendorffperfused hearts
Regional
ischemia by
coronary
artery ligation
Diazoxide (50 ␮M)
Diazoxide decreased the
incidence of ischemiainduced arrhythmias
542
Rat
Isolated,
Langendorffperfused hearts
(dual-perfusion
cannula)
Regional
ischemia
Levcromakalim (3–30 ␮M)
Levcromakalim was antiarrhythmic, regardless
whether applied to ischemic
or nonischemic tissue
128
Rat
Isolated,
Langendorffperfused hearts
Regional
ischemia by
coronary
artery ligation
Nicorandil (1–100 ␮M)
Nicorandil decreased the
incidence of PVBs and VT
(but not VF) during
ischemia
434
Rat
In vivo
Coronary artery
ligation
Diazoxide (10 mg/kg)
Diazoxide decreased the
incidence of ischemiainduced arrhythmias
509
Dog
Unanesthetized dogs
2-min coronary
occlusion
during
exercise
Glibenclamide (10 mg/kg iv)
VF was prevented in 13 of 15
animals tested
70
Dog
Anaesthetized dogs
Coronary artery
ligation
Levcromakalim (3 ␮g/kg
over 30 min)
Levcromakalim did not
increase the incidence of
ischemia-induced
arrhythmias
840
Dog
Anaesthetized dogs
Coronary artery
ligation
Nicorandil (0.2mg/kg)
Nicorandil was not
proarrhythmic
569
Dog
Anaesthetized dogs
Coronary artery
ligation
Nicorandil (2.5mg/kg/min
intra-coronary infusion)
Nicorandil decreased the
incidence of ischemiainduced VPBs and VT
839
Continued
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Mouse
KATP CHANNELS IN CARDIOPROTECTION
Table 7.—Continued
Species
Preparation
Intervention
Compound
Result
Reference
Nos.
Arterially perfused
left ventricular
wedges
Global ischemia
Nicorandil (10 or 30 ␮M)
Nicorandil prevents VT during
acute global ischemia
352
Dog
In vivo, open chest
25 min of
coronary
artery ligation
Diazoxide (intracoronary
infusion, 1 mg/kg)
Diazoxide decreased the
incidence of VPBs, VT, and
VF compared with a nodrug control group
841
Guinea
pig
Arterially perfused
right ventricular
wall
Global ischemia
Glibenclamide (1 or 10 ␮M)
or pinacidil (1 or 10 ␮M)
Glibenclamide was
proarrhythmic and pinacidil
was antiarrhythmic
133
Guinea
pig
Coronary-perfused
right ventricular
wall
Global ischemia
Glibenclamide (1 ␮M) or the
KCO NIP-121 (0.3 ␮M)
NIP-121 prevented and
glibenclamide aggravated
reperfusion-induced
arrhythmias
789
Guinea
pig
Right ventricular free
wall
“Regional”
simulated
ischemia
Glibenclamide (10 ␮M) or
the KCO bimakalim (1
␮M)
Glibenclamide inhibited the
⬙border zone⬙ arrhythmias
and bimakalim favored
these arrhythmias
639
Rabbit
Anesthetized animals
Regional
ischemia
Glibenclamide (3–24 mg/kg
iv)
Glibenclamide significantly
reduced the incidence of VF
during ischemia
51
Rabbit
Isolated,
Langendorffperfused hearts
Global ischemia
Pinacidil (1.25 ␮M)
Pinacidil accelerated the
onset of VF
111
Rabbit
Anesthetized animals
Regional
ischemia
Nicorandil (100 ␮g/kg
bolus⫹10
␮g·kg⫺1·min⫺1) or
aprikalim (10 ␮g/kg
bolus⫹0.1
␮g·kg⫺1·min⫺1)
Nicorandil and aprikalim both
reduced the incidence of
reperfusion arrhythmias.
The anti-arrhythmic effects
of the KCOs were
counteracted by
5-hydroxydecanoate
158
Rabbit
Isolated working
hearts
Regional
ischemia
Cromakalim (10 ␮M)
During ischemia, cromakalim
did not affect
arrhythmogenesis
879
Rabbit
Isolated,
Langendorffperfused hearts
Global ischemia
Cromakalim (3 ␮M)
Cromakalim accelerated the
onset, but had no effect on
the incidence, of VT and VF
during ischemia
661
Sheep
Unanesthetized,
conscious animals
Regional
ischemia
Glibenclamide (0.4 mg/kg)
Glibenclamide aggravates
reperfusion-induced
arrhythmias
593
Human
Isolated,
Langendorffperfused hearts
Pinacidil
Glibenclamide (10 ␮M)
Glibenclamide terminated
pinacidil-induced
arrhythmias
222
VT, ventricular tachycardia; VF, ventricular fibrillation; KCO, KATP channel opener; CAL, coronary artery
ligation. This table includes only a selection of a vast body of literature on this subject. We apologize to authors
that not all studies could be included. The Akar group (882a) reported recently that 30 ␮M diazoxide elicits
arrhythmias during ischemia, but only in diabetic hearts.
nel opening (for example in the peri-infarct area) is expected
to reduce the APD to cause heterogeneity in repolarization,
which is a substrate for reentrant arrhythmias (68, 869).
This may be an explanation for the antiarrhythmic effects of
KATP channel blockers ischemia (869), both in experimental
models (424, 872) and in patients with transient myocardial
ischemia or acute myocardial infarction (97, 519).
B) ELECTRICAL CONDUCTION CHANGES DURING ISCHEMIA AND THE
SPECIALIZED CARDIAC CONDUCTION SYSTEM. Electrical conduction is transiently increased within the first few minutes
after ischemia (354) (due to the increases in extracellular
K⫹) before it rapidly and progressively decreases (40, 73,
205, 394). A major cause for conduction slowing during
early ischemia is depolarization-induced reduction in the
action potential (AP) amplitude and upstroke velocity.
Conduction slowing occurs both in the working myocar-
dium and in the subendocardial layers that accommodate
the specialized CCS (394), which consists of specialized
myocytes of the AV node, bundle of His, free-running Purkinje strands, and a vast network of subendocardial Purkinje fibers. This cellular network provides rapid electrical
propagation from the AV node to the ventricular myocytes
and ensures synchronous excitation and contraction of the
entire heart. Many ventricular arrhythmias initiate in the
Purkinje fiber network, mostly through local reentrant circuits (79). During ischemia, small changes in conduction
velocity, refractory period, or conduction circuit path
length contribute to the initiation of reentrant circuits and
life-threatening arrhythmias. The AV node and distal Purkinje network are particularly sensitive to even short periods of ischemia (41). Consistently, the presence of an intact
Purkinje network is a necessary component for the initialization of VF during acute regional ischemia (393). Under-
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Dog
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
C) TERMINATION OF ARRHYTHMIAS BY BLOCKING KATP CHANNEL ACTIVITY.
From the preceding paragraph, it is clear that KATP
channel opening is a potential arrhythmogenic substrate. Experimental studies are underway to explore the underlying
arrhythmogenic mechanisms of KATP channel opening (68).
There are several studies to show that blocking KATP channels
with glibenclamide or 5-HD decreases the incidence of ischemia-induced arrhythmias or to have an antifibrillatory effect
by decreasing the duration of ventricular fibrillation (TABLE 7).
This antiarrhythmic effect is exacerbated by the KATP channeldependent action potential duration dispersion and refractoriness between the normal and ischemic tissues. Regional dispersion has also been noted to occur between the left and right
ventricles in guinea pig heart (629), but not in the Langendorff-perfused ischemic dog heart (797). In nonischemic, cardiomyopathic Langendorff-perfused human hearts, glibenclamide was found to terminate ventricular fibrillation (VF)
(218), leading to the concept that KATP channel opening participates in the maintenance of VF. They may do so by stabilizing rotor dynamics during VF, as suggested from a study
performed in pigs (650). Thus the stage is set for future studies
216
to determine whether KATP channel block may represent a
viable therapeutic antiarrhythmic target.
5. KATP channel also protect against injury during
ischemia and reperfusion
Upon coronary occlusion, cardiac ischemia not only results
in K⫹ efflux and the electrophysiological changes discussed
above. Additionally, among others, cardiac function rapidly deteriorates, intracellular pH falls, biochemical
changes take place (e.g., inorganic phosphate levels increase, CrP levels decrease, and lactate is formed), changes
occur in lipid metabolism, and oxygen free radical formation occurs. During reperfusion after short periods of acute
ischemia, contractile function recovers (at least partially).
Ischemia ultimately results in cellular necrosis and the formation of an infarct. The severity of ischemia is often measured by the rate and magnitude of postischemic contractile
recovery (i.e., during reperfusion) and by the size of the
infarct that forms. KATP channels affect both. This is a potentially important clinical finding, given that the major
determinant of the long-term prognosis in patients that survive an ischemic event is the size of the infarct. Understanding the mechanisms involved in cardioprotection and infarct size development may therefore have important therapeutic benefits.
A) PROTECTION AGAINST CONTRACTILE DYSFUNCTION DURING REPERFUSION. A large number of studies have been performed to
examine the anti-ischemic effects of KATP channel openers
(338, 622). The overwhelming majority of the studies demonstrate that KCOs delay the onset of rigor contracture
during ischemia and improve contractile recovery of the
heart during postischemic reperfusion (TABLE 8). The protective effect ranges over a variety of species, from rodents
to dogs, and appears to be independent of the experimental
preparations used (in vivo, isolated heart preparations and
in vitro preparations). The anti-ischemic effect is evident
with structurally diverse compounds, including nicorandil,
aprikalim, cromakalim, levcromakalim, diazoxide, HMR
1883, P-1075, Y-26763, and pinacidil. In the vast majority
of the studies, the protective effects of KCOs are absent (or
mitigated) in the presence of KATP channel blockers (glibenclamide or 5-hydroxydecanoate), suggesting that the protective effects are mediated by KATP channels. In most of the
studies, the KCOs were applied before the onset of ischemia. When applied after the ischemic period (i.e., when
applied only during the reperfusion period), the KCOs had
no beneficial effect to improve postischemic contractile recovery (32, 690). Other indexes of ischemic damage were
also investigated in some of the studies. For example, cromakalim and P-1075 reduced lactate dehydrogenase (LDH)
and creatine kinase (CK) release during postischemic reperfusion (300, 301, 690, 782) or decreased lactate excretion
in the coronary effluent (730). When applied during the
ischemic period, the KCOs also have an ATP-sparing effect
(see sect. IXB8). Compounds with KATP channel blocking
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standing the properties of the CCS during ischemia potentially offers therapeutic opportunities for the treatment of
this type of arrhythmia. KATP channels appear to have some
role. KATP channels are expressed in the SA node and CCS
and affect the functional properties of these cells during
metabolic stress (415, 502, 696). For example, hypoxiainduced bradycardia is mediated by KATP channel opening
(248, 498). Moreover, hypoxia-induced conduction slowing in Langendorff-perfused rabbit hearts is prevented by
the KATP channel blocker glibenclamide (698). In dog heart,
intramyocardial conduction delay induced by ischemia is
reduced by glibenclamide (61). Glibenclamide also decreases the incidence of ischemia-induced transmural conduction block in a canine wedge preparation (633), prevents the increased longitudinal resistance (electrical uncoupling) in an isolated rabbit septal preparation during
ischemia (787), and prevents the subendocardial conduction delay produced by ischemia in an isolated, arterially
perfused canine interventricular septal preparation (576).
CCS KATP channels are therefore likely to participate in
ischemia-induced conduction disturbances, and their opening may precipitate life-threatening arrhythmias. The situation may be aggravated by the regional distribution of
KATP channels. For example, KATP channels may contribute
to the left-right ventricular electrical heterogeneity in
guinea pig hearts during global ischemia [but not in the dog
heart (797)], mainly due to the higher KATP channel density
in the left ventricle (629). Simulation studies further predict
that transmural gradients of KATP channel density may contribute to activation rate gradients and arrhythmogenicity,
with a potential role for the Purkinje system in causing local
endocardial spatial heterogeneity, which may serve as an
arrhythmogenic trigger (80).
KATP CHANNELS IN CARDIOPROTECTION
activity, such as glibenclamide, 5-hydroxydecanoate, HMR
1098, or tolbutamide, when applied alone (in the absence of
KCOs) exacerbate ischemic damage, evident as a more severe ischemic contracture and worsening of postischemic
contractile recovery in most, but not all, studies (32, 133,
251, 272, 300, 336, 566, 897). Thus a large body of literature suggests that opening KATP channels during ischemia is
cardioprotective.
B) PROTECTION AGAINST THE DEVELOPMENT OF AN INFARCT.
C) PROTECTION AGAINST THE DECLINE OF CELLULAR HIGH-ENERGY
PHOSPHATES DURING ISCHEMIA.
During the first few minutes of
acute myocardial ischemia, a rapid loss of intracellular creatine phosphate levels occurs, which is followed by a more
gradual (over the next 5–10 min) decline of ATP levels and
an increase of ADP and AMP levels (233, 375). The antiischemic effects of KATP channel opening may translate to
preservation of high-energy phosphate compounds during
ischemia. Indeed, during ischemia in a guinea pig right ventricle preparation, pinacidil was found to preserve both
ATP and PCr levels in a glibenclamide-dependent manner
(556). The cardioprotective effects of cromakalim are also
accompanied by an attenuation of intracellular ATP loss
during ischemia (301). Moreover, in 31P-NMR studies, nicorandil and diazoxide were shown to mitigate ischemia-
D) DO SPECIES DIFFERENCES EXIST? An argument could be raised
that there are major differences in mice and rats compared
with other, larger animals. This may be so because rodents
have a short cardiac cycle length and they need large outward currents to repolarize the action potential and to
avoid fusion of the action potentials. Intuitively, one may
expect rodents to be extremely dependent sarcolemmal
KATP channels to survive metabolic stress and for glibenclamide to be devastating to ischemic mouse hearts (with
much less effect of the drug in species with long action
potentials). It is therefore instructive to compare the effects
of glibenclamide on ischemic contracture and cardiac functional recovery and infarct size after myocardial ischemia in
species with short (mouse and rat) and long (rabbit and
dog) action potentials. The published data are mixed (TABLE 9) and do not appear to support the notion that the
intrinsic action potential duration fundamentally changes
in the outcome. In dog, for example, infarct size is either
increased or unaffected by glibenclamide (31, 292). In some
rabbit studies, glibenclamide increased postischemic infarct
size (567, 805), whereas other studies reported no effect
(812, 813, 854). In rats, glibenclamide has no effect on
infarct size (152, 647), increases infarct size at higher concentrations that are associated with changes in blood glucose levels (511), or may even decrease infarct size in some
studies (203). Postischemic functional recovery is largely
unaffected by glibenclamide in mice and rats (653, 722,
723). Contrary to the notion that KATP channel block is
devastating to ischemic mouse hearts, infarct size and/or
functional recovery after ischemia are not markedly in-
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The
extent of an infarct after acute coronary artery occlusion is
dependent on the degree of ischemic damage. The antiischemic effects of KATP channel opening would therefore
predict a reduction in tissue damage and decreased infarct
development after a cardiac ischemic episode. Indeed, KATP
channel openers have been demonstrated to reduce postischemic infarct development (e.g., in dogs and rabbits;
TABLE 9). Infarct size reduction was observed with diverse
agents, including cromakalim, aprikalim, bimakalim,
pinacidil, and nicorandil. The cardioprotective effects of
KCOs can be blocked by the KATP channel blockers glibenclamide and 5-hydroxydecanoate. By themselves (in the absence of KCOs), these KATP channel blockers mostly have
little effect on infarct size development (TABLE 9). Not all
studies are positive, however, and it appears that the choice
of anesthetic used for the in vivo studies may affect the
cardioprotective properties of KATP channel opening (567,
584, 854). In the majority of the studies, KATP channel
openers were applied before the onset of ischemia. A few
studies examined the timing of drug application and found
that when KCOs were applied after ischemia (i.e., only
during the reperfusion period), no benefit was observed (28,
29, 297). Very few studies examined the application of
KCOs after the onset of ischemia, but before reperfusion. In
such studies, when nicorandil or bimakalim was applied
10 –15 min after induction of ischemia, they were able to
reduce infarct size (209, 294, 475, 900). Overall, the majority of studies demonstrate that KATP channels have an
important role in the protection of the myocardium from
ischemia-reperfusion injury.
induced ATP depletion and Pi accumulation and to reduce
intracellular Na⫹ accumulation during ischemia (182, 247,
852). Total myocardial metabolite levels during ischemia
are also preserved by nicorandil (640; but see Ref. 566).
Not all studies are in agreement. Other studies found that,
although pinacidil and diazoxide protected against postischemic functional decline and improved ATP and phosphocreatine levels during reperfusion, no appreciable effects were observed on ischemic ATP levels (11, 239, 247,
605). Even if ATP levels are not substantially changed, KATP
channel openers can improve the free energy of ATP hydrolysis, as demonstrated with 31P-NMR measurements in hypoxic guinea pig hearts (173). It is possible that KATP channel openers may preserve mitochondrial function during
ischemia, similar to the preservation of mitochondrial integrity that is observed with L-type Ca2⫹ channel blockers
(464, 591) and with blockers of the mitochondrial permeability transition pore (180), or by inhibiting Ca2⫹ uptake
into mitochondria (224, 254). This putative protective effect may be direct, due to effects of the KCOs on mitochondrial KATP channels (263) or on the mitochondrial F1F0ATPase (11). Protective effects of KCOs on mitochondria
may also be indirect, for example, by reducing Ca2⫹ uptake
into cardiomyocytes (and presumably Ca2⫹-induced mitochondrial damage) (142, 480, 764).
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Table 8. Effects of KATP channel modulators on postischemic functional recovery
Species
Preparation
Intervention
Compound
Result
Reference
Nos.
Anesthetized
animals
15 min CAL and 3 h
reperfusion
Nicorandil (100 ␮g/kg ⫹ 25
␮g·kg⫺1·min⫺1) or
glibenclamide (0.3 mg/kg)
Nicorandil accelerated recovery of segment
shortening in the ischemic/reperfused
region. Glibenclamide prevented the
protective effect of nicorandil, but had no
effect on functional recovery by itself
27
Dog
Anesthetized
animals
15 min CAL and 3 h
reperfusion
Aprikalim (10 ␮g/kg plus 0.1
␮g·kg⫺1·min⫺1)
Aprikalim improved postischemic function
32
Dog
Anesthetized
animals
15 min CAL and 3 h
reperfusion
Cromakalim (1 ␮g·kg⫺1·min⫺1
intracoronary)
Cromakalim led to improved postischemic
contractile function
149
Dog
Anesthetized
animals
30 min CAL and 3 h
reperfusion
Nicorandil (100-␮g/kg bolus
followed by 25
␮g·kg⫺1·min⫺1 iv)
Nicorandil-treated animals showed an
improvement in myocardial segment
function through reperfusion
296
Dog
Anesthetized
animals
15 min CAL and 3 h
reperfusion
Nicorandil (0.3
␮g·kg⫺1·min⫺1
intracoronary)
Nicorandil improved reperfusion function
only when administered iv
304
Pig
Anesthetized
animals
60 min CAL and 3 h
reperfusion
Nicorandil (7.5–17.5
␮g·kg⫺1·min⫺1)
LV dP/dt recovery during reperfusion
occurred earlier with nicorandil
250
Rabbit
Anesthetized
animals
10 min CAL and 30
min reperfusion
Nicorandil (10 ␮g/kg)
Nicorandil improved postischemic recovery
of systolic thickening fraction (prevented
by glibenclamide)
385
Rabbit
Isolated,
Langendorffperfused hearts
Ischemia, followed
by 20 min
reperfusion
Cromakalim (10 ␮M)
Recovery of heart rate and LVDP were
significantly improved by cromakalim
730
Rabbit
Isolated,
Langendorffperfused hearts
20 min global
ischemia and 30
min reperfusion
Aprikalim (100 ␮M)
Aprikalim resulted in significantly better
postischemic recovery of function
131
Rat
Isolated, working
hearts
10–35 min low-flow
ischemia and 15
min reperfusion
Tolbutamide (0.06–0.9 mM)
Tolbutamide improved postischemic
functional recovery (0.6 mM was
optimal)
701
Rat
Isolated,
Langendorffperfused hearts
25 min global
ischemia and 30
min reperfusion
Pinacidil (1–100 ␮M) or
cromakalim (1 or 7 ␮M)
Pinacidil and cromakalim improved
postischemic recovery of LVDP
300
Rat
Isolated,
Langendorffperfused hearts
30 min global
ischemia and 30
min reperfusion
Cromakalim (10 ␮M)
Cromakalim improved recovery of LVDP
during reperfusion
782
Rat
Isolated,
Langendorffperfused hearts
25 min global
ischemia and 30
min reperfusion
BMS-180448 (1–30 ␮M)
and/or glibenclamide (1
␮M)
BMS-180448 (⬎3 ␮M) improved recovery
of LVDP during reperfusion (which was
blocked by glibenclamide). By itself,
glibenclamide had no effect
299
Rat
Isolated,
Langendorffperfused hearts
25 min total global
ischemia and 45
min reperfusion
Cromakalim (10 ␮M)
Cromakalim delayed the time to ischemic
contracture and improved recovery of
function during reperfusion
182
Rat
Isolated,
Langendorffperfused hearts
25 min global
ischemia and 30
min reperfusion
P-1075 (10–300 nM)
P-1075 improved recovery of contractile
function
690
Rat
Isolated, working
hearts
28 min of global
ischemia followed
by 30 min
reperfusion
Y-26763 (1 ␮M)
Y-26763 improved recovery of
postischemic cardiac function and
reduced enzyme leakage (glibenclamide
prevented these effects)
653
Rat
Isolated,
Langendorffperfused hearts
25 min global
ischemia and 30
min reperfusion
Aprikalim (1–100 ␮M)
Aprikalim improved reperfusion contractile
function and reduced lactate
dehydrogenase release
298
Rat
Isolated,
Langendorffperfused hearts
25 min global
ischemia and 30
min reperfusion
Cromakalim (0.3–100 ␮M)
The (⫺)-stereoisomer is 50–100 times
more potent to delay ischemic
contracture (EC25 ⬃2 ␮M) and to
improve contractile recovery during
reperfusion
301
Rat
Isolated,
Langendorffperfused hearts
25 min global
ischemia and 30
min reperfusion
Diazoxide (1–100 ␮M) or
cromakalim (1–100 ␮M
Diazoxide and cromakalim increased the
time to onset of contracture with a
similar potency and improved
postischemic functional recovery in a
glibenclamide-reversible manner
262
Rat
Isolated,
Langendorffperfused hearts
20–30 min ischemia
and 40 min
reperfusion
Levcromakalim (10 ␮M)
Levcromakalim decreased the time to
contractile arrest during ischemia,
delayed contracture, and improved the
recovery of LVDP during reperfusion
251
Rat
Isolated,
Langendorffperfused hearts
20 min low-flow
ischemia and 30
min reperfusion
Nicorandil (7 ␮M)
Nicorandil led to improved functional
recovery during reperfusion
294
Rat
Isolated,
Langendorffperfused hearts
30 min CAL and 30
min reperfusion
HMR 1098 (30 ␮M) or 5hydroxydecanoate (100
␮M)
Both HMR 1098 and 5-HD depressed
LVDP postischemic recovery
272
Continued
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KATP CHANNELS IN CARDIOPROTECTION
Table 8.—Continued
Species
Preparation
Intervention
Compound
Result
Reference
Nos.
Rat
Anesthetized
animals
28 min global
ischemia and 30
min reperfusion
Glibenclamide (10 ␮M) infused
into the atrium
Glibenclamide had no effect on LVDP
postischemic recovery
653
Mouse
Isolated,
Langendorffperfused hearts
20 min global noflow ischemia,
followed by 40
min reperfusion
Glibenclamide (1 ␮M) or 5hydroxydecanoate (100
␮M)
LVDP postischemic recovery was
unaffected by either compound
723
Mouse
Isolated,
Langendorffperfused hearts
20 min global noflow ischemia,
followed by 40
min reperfusion
Glibenclamide (20 ␮M), 5hydroxydecanoate (100
␮M), or pinacidil (100 ␮M)
Glibenclamide or 5-HD caused a small but
significant reduction in postischemic
LVDP recovery in WT hearts, whereas
pinacidil markedly improved functional
recovery
722
Guinea
pig
Arterially perfused
right ventricular
wall
20–30 min ischemia
and 60 min
reperfusion
Pinacidil (1–10 ␮M)
Pinacidil led to improved recovery of
electrical and mechanical activity during
reperfusion
133
creased in Kir6.2 knockout mice (which lack cardiac sarcolemmal KATP channels) compared with wild-type mice
(771, 856). Collectively, these data indicate that species
with an inherently short cardiac action potential (such as
mice and rats) are not more dependent on KATP channels to
protect against stress than other species with inherently longer action potentials (such as rabbits, dogs, and perhaps
humans).
6. Preconditioning of the myocardium as a protective
mechanism
One or more brief ischemic episodes protect the heart from
a subsequent sustained ischemic insult (582). This endogenous form of cardioprotection, named ischemic preconditioning, has been the subject of many investigations in an
attempt to elucidate the underlying mechanisms, which (if
understood) have potential therapeutic benefits for the
treatment or prevention of myocardial ischemia and infarction. The reader is referred to reviews on the subject for a
full description of preconditioning, the underlying mechanisms, and cellular pathways involved (130, 581, 756, 895,
903). Preconditioning can also be elicited by pharmacological compounds or receptor agonists (such as adenosine)
(507), and this type of protection is often referred to as
“pharmacological preconditioning.” Volatile anesthetics
also have a preconditioning-like effect on the ischemic heart
(772). The early phase of preconditioning occurs 1–3 h after
the conditioning stimulus, but there is also a delayed phase,
which occurs after 18 –24 h and can continue for as long as
24 –72 h (757). KATP channels appear to have an important
role in most, if not all, in the cardioprotection resulting
from these forms of preconditioning. TABLE 10 lists a small
selection of a very large body of literature to study the
effects of KATP channel modulating agents on preconditioning. Some of the earliest mechanistic studies found that
ischemic preconditioning slows energy metabolism during
the subsequent sustained (or index) ischemic period (583).
Soon afterwards, signaling through adenosine receptors
was found to mediate the protective effect of ischemic preconditioning (507). The description that blockade of KATP
channels with glibenclamide prevented myocardial preconditioning in dogs (292) set in motion an avalanche of studies
to examine the role(s) of KATP channel modulators in various forms of preconditioning. Initially, conflicting data appeared from different laboratories (133, 300, 442, 805).
The negative reports in some studies might have been due
partly to off-target effects of the KCOs (e.g., coronary
steal), but it was soon appreciated that the choice of anesthetics used also play a major role (854). Today, with hundreds of citations in Pubmed on this subject, the consensus
is that certain compounds with KATP channel blocking activity such as glibenclamide and 5-hydroxydecanoate mitigate the protective effects of ischemic preconditioning on
infarct size, whereas others such as HMR-1098 (at least in
some studies) are less effective against early ischemic preconditioning (TABLE 10). Glibenclamide, 5-hydroxydecanoate, and HMR-1098 also block the protective effects of
late preconditioning (65, 559, 635, 811). The converse is
also true: structurally diverse compounds with KATP channel opening activity, including aprikalim, bimakalim,
pinacidil, nicorandil, or diazoxide, are cardioprotective by
reducing the size of the developing infarct when they are
applied before index ischemia (i.e., given instead of the
preconditioning ischemia). The protective effects of these
compounds are only evident when applied before (or early
during) the index ischemia, and these protective effects can
be reversed by coadministration of compounds with KATP
channel blocking activity (TABLE 10).
7. Interpretation of the data: which KATP channels
are involved in cardioprotection?
In the majority of studies, KATP channel openers are cardioprotective during cardiac ischemia (TABLES 8–10). While
KATP channel blockers are not necessarily detrimental, they
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CAL, coronary artery ligation; LV, left ventricle/ventricular; LVDP, left ventricular developed pressure.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Table 9. Effects of KATP channel modulators on post-ischemic infarct size
Species
Preparation
Intervention
Compound
Result
Reference
Nos.
Anesthetized animals
90 min CAL and 5 h
reperfusion
Cromakalim (0.1 ␮g·kg⫺1·min⫺1
intracoronary infusion)
Cromakalim reduced infarct size
302
Dog
Anesthetized animals
90 min CAL and 5 h
reperfusion
Aprikalim (10 ␮g/kg ⫹0.1
␮g·kg⫺1·min⫺1 iv) or
glibenclamide (1 mg/kg; iv
bolus)
Infarct size was reduced by
aprikalim and was increased by
glibenclamide
31
Dog
Anesthetized animals
60 min CAL and 5 h
reperfusion
Aprikalim (10 ␮g/kg ⫹0.1
␮g·kg⫺1·min⫺1 iv) or
glibenclamide (0.3 mg/kg; iv
bolus)
Aprikalim reduced infarct size. By
itself, glibenclamide was without
effect on infarct size
292
Dog
Anesthetized animals
90 min CAL and 5 h
reperfusion
Cromakalim (0.2
␮g·kg⫺1·min⫺1)
Cromakalim did not reduce infarct
size
442
Dog
Anesthetized animals
90 min CAL and 5 h
reperfusion
Bimakalim (3 ␮g/kg ⫹0.1
␮g·kg⫺1·min⫺1 iv)
Bimakalim reduced infarct size
29
Dog
Anesthetized animals
2 h CAL and 30 min
reperfusion
Nicorandil 100 ␮g/kg ⫹25
␮g·kg⫺1·min⫺1) or bimakalim
3 ␮g/kg ⫹0.1
␮g·kg⫺1·min⫺1)
Both nicorandil and bimakalim
reduced infarct size
294
Dog
Anesthetized animals
3 h ischemia
Nicorandil (100 ␮g/kg ⫹30
␮g·kg⫺1·min⫺1)
Nicorandil reduced infarct size
209
Dog
Anesthetized animals
90 min CAL and 5 h
reperfusion
Pinacidil (0.9 ␮g·kg⫺1·min⫺1
intracoronary infusion)
Pinacidil decreased infarct size
297
Rabbit
Anesthetized animals
30 min CAL followed
by 180 min
reperfusion
Glibenclamide (0.15–3 mg/kg)
or pinacidil (0.5–1.0 mg/kg)
Glibenclamide significantly increased
infarct size at each concentration
tested. Pinacidil had no effect
805
Rabbit
Anesthetized animals
30 min CAL followed
by 120 min
reperfusion
Glibenclamide (3 mg/kg)
Glibenclamide by itself had no effect
on infarct size, but blocked the
protective effect of IPC
812
Rabbit
Anesthetized animals
30 min CAL followed
by 180 min
reperfusion
Glibenclamide (0.3 mg/kg) or
pinacidil (1.0 mg/kg)
Glibenclamide by itself had no effect
on infarct size. Pinacidil reduces
infarct size
854
Rabbit
Anesthetized animals
30 min CAL and 120
min reperfusion
Nicorandil (100 ␮g/kg bolus
⫹10 ␮g·kg⫺1·min⫺1) or 5-HD
(5 mg/kg)
Nicorandil reduced infarct size. By
itself, 5-HD has no effect on
infarct size
368
Rabbit
Anesthetized animals
30 min CAL and 48 h
reperfusion
Nicorandil (10 ␮g·kg⫺1·min⫺1)
Preischemic but not postischemic
administration of nicorandil
reduced the size of myocardial
infarct
614
Rabbit
Anesthetized animals
30 min CAL
Bimakalim (3 ␮g/kg ⫹0.1
␮g·kg⫺1·min⫺1) or nicorandil
(100 ␮g/kg ⫹10
␮g·kg⫺1·min⫺1) or 5-HD (5
mg/kg)
Both nicorandil and bimakalim
resulted in a decreased infarct
size. 5-Hydroxydecanoate alone
did not affect infarct size
157
Rabbit
Anaesthetized
animals
(halothane)
40 min CAL and 120
min reperfusion
Nicorandil (100 ␮g·kg⫺1·min⫺1,
for 10 min) or 5-HD (5 mg/
kg iv)
Neither nicorandil nor 5-HD alone
affected infarct size
584
Rabbit
Isolated,
Langendorffperfused hearts
30 min global ischemia
and 120 min
reperfusion
Nicorandil (100 ␮M)
Nicorandil significantly reduced
infarct size, which was blocked by
HMR 1098 (5 ␮M) or 5-HD (100
␮M). 5-HD or HMR 1098 alone
had no effects on infarct size
818
Rat
Anesthetized animals
30 min CAL and 90
min reperfusion
Glibenclamide (0.3 mg/kg)
By itself, glibenclamide had no effect
on infarct size, but it blocked the
infarct-limiting effect of IPC or
acetylcholine
647
Rat
Anesthetized animals
30 min CAL and 120
min reperfusion
Glibenclamide (3 mg/kg)
Glibenclamide caused an increase in
infarct size (note: blood glucose
was significantly decreased)
511
Rat
Isolated,
Langendorffperfused hearts
35 min CAL and 120
min reperfusion
Glibenclamide (1 ␮M)
Glibenclamide had no effect on
infarct size by itself, but
prevented the infarct limiting
effect of BNP
152
CAL, coronary artery ligation; 5-HD, 5-hydroxydecanoate.
generally abolish the protective effects of the KATP channel
openers. Although the data are indisputable, the interpretation of these data has given rise to conflicting views,
mostly related to the nature of the KATP channel subtype
that is responsible for ischemic cardioprotection. A variety
of KATP channel subtypes exist in the cardiovascular system
220
(see sect. VII), each with unique functions in various regions
of the heart and specialized conduction system, smooth
muscle, and endothelium. Moreover, these channels have
overlapping pharmacological profiles (TABLE 3). Despite
this diversity, most studies attempt to discriminate between
the protective roles of sarcolemmal and mitochondrial KATP
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KATP CHANNELS IN CARDIOPROTECTION
channels in the ventricular myocyte. Although the arguments can be complex, the key arguments in the debate of
roles for/against these channels can be summarized as follows.
A) DIAZOXIDE IS A SPECIFIC MITOCHONDRIAL
KATP
CHANNEL
OPENER. There are ⬎100 studies in the cardiac precondition-
5-HD SELECTIVELY BLOCKS SPECIFIC TYPES OF KATP CHANNELS.
5-HD is often employed in cardioprotection studies as a
specific mitochondrial KATP channel blocker (43, 780). This
contention appears to rely mainly of the ability of 5-HD to
reverse diazoxide-induced K⫹ fluxes in reconstituted heart
mitochondrial preparations (262) and to attenuate diazoxide-induced changes in autofluorescence of isolated cardiomyocytes (513, 693). This argument ignores the fact that
5-HD blocks (with an IC50 of 0.16 –28 ␮M) KATP channels
recorded in the inside-out configuration in isolated patches
from cardiac ventricular myocytes (497, 609). 5-HD also
B)
KATP
The basis of this argument
is that mice genetically deficient in sarcolemmal KATP channel subunits are less protected against ischemic insults;
hence, sarcolemmal KATP channels must be cardioprotective. Indeed, the protective effect of ischemic preconditioning to reduce infarct size or to improve postischemic functional recovery was readily observed in wild-type mice, but
was absent in Kir6.2⫺/⫺ mice (771, 876). As noted above,
the preconditioning-like cardioprotective effect of diazoxide is similarly lost in the Kir6.2⫺/⫺ mice (770, 876). Moreover, the protective effect of late preconditioning, induced
by pretreatment with the A3 AR agonist CP-532,903, is
absent in the hearts of Kir6.2⫺/⫺ mice (856). Knockout of
Kir6.2 worsens myocardial Ca2⫹ load in vivo and impairs
functional recovery after ischemia (305). It also negates
ischemic preconditioning-induced protection of myocardial
energetics (306). Consistent with these data, transgenic
overexpression of SUR2A in mice generates a cardiac phenotype resistant to ischemia (189). These genetic studies
provide powerful arguments for a role of sarcolemmal KATP
channels in cardioprotection, but these arguments must be
interpreted by keeping in mind two caveats. First, these
studies are all performed using mice, which have a high
metabolic rate and abbreviated action potentials. Although the shorter action potential of mice per se does
not seem to makes a difference with regard to the response to ischemia-induced injury (see above), species
differences can be important when considering metabolic
effects or other electrophysiological responses (e.g., the
development of arrhythmias). Second, these arguments
assume that Kir6.2/SUR2A subunits exclusively form the
ventricular sarcolemmal KATP channels, which may be a
simplistic view, given some reports of their expression in
C) GENETIC MOUSE MODELS SHOW THAT SARCOLEMMAL
CHANNELS ARE CARDIOPROTECTIVE.
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ing literature that employed diazoxide as a specific opener
of mitochondrial KATP channels and/or used 5-HD as a
specific mitochondrial KATP channel blocker. Indeed, in isolated mitochondria, diazoxide opens the mitochondrial
KATP channel with an EC50 of 2–27 ␮M (263, 512, 876)
and has little effect on ventricular sarcolemmal KATP channels under basal conditions. The potent cardioprotective
properties of diazoxide are therefore often taken as evidence for a contribution of mitochondrial KATP channels in
cardioprotection. Counterarguments can be leveled, including the fact that ventricular sarcolemmal KATP channels
become sensitive to diazoxide under metabolically impaired
conditions, as occurs during myocardial ischemia (151,
546), as evidenced by the fact that the rate of action potential duration shortening during the first 10 min of ischemia
is accelerated by the compound (at least in some studies;
TABLE 6). The interpretation of data obtained with diazoxide is therefore not straightforward. The fact is that diazoxide neither exhibits specificity (the capacity of a drug to
have a unique action) since it affects blood pressure and
blood glucose levels as well as contributes to cardioprotection, nor selectivity (the ability of a drug to affect a particular molecular target in preference to others) since it affects
several types of KATP channels and also have other offtarget effects (125). Moreover, diazoxide affects these various effectors within the range of concentrations that are
commonly used in cardioprotection studies (125). A strong
argument in favor of the sarcolemmal KATP channel as a
diazoxide target comes from the observation that the cardioprotective effect of diazoxide is blunted or lost in mice
lacking Kir6.2, a known subunit of the sarcolemmal KATP
channel (770, 876). Assigning a single molecular target to
diazoxide=s protective effect is therefore not a simple matter, and the possibility must be considered that diazoxide
has multiple effectors that may synergistically contribute to
this compound=s powerful cardioprotective properties
(125).
effectively blocks ventricular KATP channel currents in the
whole cell configuration (608). Moreover, as one would
expect from its ability to block KATP channels, 5-HD partially inhibits K⫹ efflux from the ischemic heart (600, 681)
and mitigates action potential duration shortening during
cardiac ischemia (TABLE 6). Curiously, 5-HD had no effect
on the negative inotropic effects of cromakalim in the absence of ischemia, but completely reversed its cardioprotective effects, which led to the suggestion that 5-HD is an
ischemia-selective KATP channel inhibitor (552). Off-target
effects of 5-HD are also possible since 5-HD can be activated to 5-HD CoA in mitochondria and metabolized by
the ␤-oxidation pathway, but also blocks ␤-oxidation of
other fatty acids (see sect. VI). Thus, although 5-HD is very
effective at mitigating the protective effect of ischemic or
pharmacological preconditioning (TABLE 10), the drug
lacks selectivity: published data show that it blocks both
mitochondrial and sarcolemmal KATP channels, and it is no
easy task to assign a specific molecular target to this compound.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Table 10. Effect of KATP channel modulators on ischemic preconditioning
Species
Preparation
PC
Ischemia
Compound
Result
Reference
Nos.
Anesthetized
animals
1 x 5 min
60 min regional
ischemia and 5 h
reperfusion
Glibenclamide (0.3 mg/kg)
or aprikalim (10 ␮g/kg
plus 0.1 ␮g/kg iv)
Glibenclamide prevented infarct
size reduction of IPC when
applied before or after IPC,
but had no effect on its own.
Aprikalim reduced infarct
size in the absence of IPC.
292
Dog
Anesthetized
animals
1 x 5 min
60 min regional
ischemia and 5 h
reperfusion
Glibenclamide (5
␮g·kg⫺1·min⫺1) or R-PIA
(0.4 ␮g·kg⫺1·min⫺1 ic)
Glibenclamide prevented infarct
size reduction of IPC or A1
receptor stimulation
303
Dog
Anesthetized
animals
1 x 5 min
60 min regional
ischemia and 5 h
reperfusion
5-HD (150 ␮g·kg⫺1·min⫺1
ic) or glibenclamide (3
␮g·kg⫺1·min⫺1 ic)
Both 5-HD and glibenclamide
prevented infarct size
reduction of IPC when
applied before or after IPC
3)
Dog
Anesthetized
animals
1 x 10 min
60 min regional
ischemia and 4 h
reperfusion
Adenosine (400 ␮g/min),
glibenclamide (0.3 mg/
kg iv), or 5-HD (3 mg/
min ic)
Adenosine elicits reduction in
infarct size. 5-HD and
glibenclamide prevented
infarct size reduction of IPC
or adenosine.
899
Dog
Anesthetized
animals
1 x 10 min
60 min regional
ischemia and 4 h
reperfusion
Bimakalim (0.3 ␮g/min ic)
Bimakalim enhanced the ability
of IPC to reduce infarct size.
It also markedly accelerated
the ischemia-induced
shortening of the action
potential during IPC
898
Dog
Anesthetized
animals
1 x 10 min
60 min regional
ischemia and 4 h
reperfusion
Bimakalim (1 ␮g/kg plus
0.05 ␮g·kg⫺1·min⫺1 iv)
Bimakalim, applied before
ischemia or 10 min prior to
reperfusion, resulted in
reductions in infarct size and
adenosine release to a
similar extent as IPC
570
Dog
Anesthetized
animals
MLA 24 h before
ischemia
60 min regional
ischemia and 3 h
reperfusion
Glibenclamide (0.3 mg/kg
iv) or 5-HD (7.5 mg/kg
ic over 20 min)
Both glibenclamide and 5-HD
block the infarct size
reduction of late
preconditioning induced by
MLA
559
Dog
Anesthetized
animals
Desflurane
60 min regional
ischemia and 3 h
reperfusion
Glibenclamide (0.1 mg/kg
iv) or HMR 1098 (1
␮g·kg⫺1·min⫺1) or 5-HD
(150 ␮g·kg⫺1·min⫺1)
Glibenclamide, HMR 1098 and
5-HD abolished the
protective effects of volatile
anesthetic-induced
preconditioning on infarct
size. By themselves, HMR
1098 and 5-HD had no
effect on infarct size.
808
Pig
Anesthetized
animals
1 x 10 min
90 min regional
ischemia and 2 h
reperfusion
Glibenclamide (0.5 mg/kg,
followed by 50 ␮g/min
iv)
Glibenclamide blocked the
protective effect of IPC on
infarct size. By itself,
glibenclamide did not affect
infarct size.
706
Pig
Anesthetized
animals
2 x 5 min
30 min regional
ischemia and 3 h
reperfusion
5-HD (5 mg/kg iv) or
diazoxide (3.5 mg/kg, 1
ml/min iv)
The infarct size reduction of
IPC was not blocked by 5HD. Diazoxide limits infarct
size and this effect is blocked
by 5-HD.
713
Pig
Anesthetized
animals
2 x 10 min
30 min regional
ischemia and 90
min reperfusion
5-HD (0.2 mg·kg⫺1·min⫺1
ic) or R-PIA (2.5
␮g·kg⫺1·min⫺1)
IPC and R-PIA reduced infarct
size. 5-HD by itself did not
affect infarct size, but
blocked the infarct size
reduction of R-PIA
834
Ferret
Anesthetized
animals
2 or 5 min
ischemia
60 min regional
ischemia and 5 h
reperfusion
BMS-180448 (2 mg/kg)
or glyburide (0.2
mg·kg⫺1·min⫺1) or 5HD (10 mg·kg⫺1·min⫺1)
BMS-180448 and IPC reduced
infarct size. The infarct-size
reduction of IPC was blocked
by glibenclamide and 5-HD
275
Rabbit
Anesthetized
animals
1 x 5 min
30 min regional
ischemia and 2 h
reperfusion
Glibenclamide (0.3 mg/kg)
Glibenclamide blocked the
protective effect of IPC on
infarct size. By itself,
glibenclamide did not affect
infarct size.
812
Rabbit
Anesthetized
animals
1x10 min
30 min regional
ischemia and 3 h
reperfusion
Pinacidil (0.3 mg/kg iv) or
glibenclamide (0.3 mg/
kg iv)
Both pinacidil and IPC reduced
infarct size. Glibenclamide
blocked the infarct size
reduction of IPC
854
Rabbit
Anesthetized
animals
1 x 10 min
60 min regional
ischemia and 2 h
reperfusion
5-HD (5 mg/kg)
5-HD blocked the protective
effect of IPC to reduce
infarct size
348
Rabbit
Anesthetized
animals
1 x 5 min
30 min regional
ischemia and 3 h
reperfusion
Diazoxide (10 mg/kg) or
5-HD (5 mg/kg)
Both IPC and diazoxide reduced
infarct size. 5-HD blocked
the infarct size reduction
caused by diazoxide
43
Continued
222
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Dog
KATP CHANNELS IN CARDIOPROTECTION
Table 10.—Continued
Species
Preparation
PC
Ischemia
Compound
Result
Reference
Nos.
Anesthetized
animals
None
20 min regional
ischemia and 2 h
reperfusion
Nicorandil (0.47 mg/kg),
pinacidil (0.1 mg/kg),
5-HD (5 mg/kg), or
HMR 1883 (3 mg/kg)
The infarct-reducing effects of
nicorandil and pinacidil were
abolished by 5-HD, but not
by HMR 1883
156
Rabbit
Anesthetized
animals
6 x 4 min, 24 h
before index
ischemia
30 min regional
ischemia and 3
days reperfusion
Nicorandil (100 ␮g/kg
bolus ⫹30
␮g·kg⫺1·min⫺1 iv for 60
min)
Both late preconditioning and
nicorandil-pretreatment
caused a reduction in infarct
size
792
Rat
Anesthetized
animals
1 x 5 min
30 min regional
ischemia and 2 h
reperfusion
HMR-1098 (3 or 6 mg/
kg) or 5-HD (10 mg/kg)
5-HD was more effective than
HMR-1098 to reverse the
protective effect of IPC on
infarct development. By
themselves, 5-HD or HMR1098 had no effect.
245
Rat
Anesthetized
animals
1 x 5 min 24 h
before index
ischemia
30 min regional
ischemia and 2 h
reperfusion
HMR-1098 (6 mg/kg) or
5-HD (10 mg/kg)
HMR-1098, but not 5-HD,
abolished the infarct size
reduction of late IPC
635
Mouse
Isolated, perfused
hearts
IB-MECA
30 min of global
ischemia and 30
min of
reperfusion
5-HD (200 ␮M)
The A3AR agonist IB-MECA
reduced infarct size. This
protective effect was
prevented by 5-HD.
929
Mouse
Anesthetized
animals
CP-532,903
30 min regional
ischemia and 2 h
reperfusion
None
The A3AR agonist CP-532,903
reduced infarct size. The
cardioprotective effects of
CP-532,903 were absent in
the hearts of Kir6.2⫺/⫺
mice
856
PC, preconditioning; 5-HD, 5-hydroxydecanoate; ic, intracoronary infusion; iv, intravenously; MLA, monophosphoryl lipid A.
mitochondria (TABLE 5) and other cardiovascular tissues
(see sect. VII).
KATP CHANThis is probably not the correct question to ask. In all likelihood, sarcolemmal and mitochondrial KATP channels, along with the
other KATP channel subtypes in the cardiac conduction system, endothelium, smooth muscle, and even noncardiovascular tissues, are all involved and they synergistically interact to protect the heart against ischemic and other stresses
(FIGURE 13). If so, this might explain the extraordinary
efficacy of diazoxide, which affects most of these KATP
channels at the concentrations used experimentally to elicit
cardioprotection (125). Moreover, although cardiac ischemia is usually characterized as a disease of the myocyte, it
is clear that the vasculature, and especially endothelial cells,
is a major target of this pathology (412, 627, 716). As is true
for cardiac myocytes, endothelial dysfunction during ischemia can be prevented by preconditioning with brief periods of intermittent ischemia (482, 627) in a KATP channeldependent manner (85, 534), thus extending to coronary
endothelial cells the concept of endogenous protection
mechanisms. Even though endothelial KATP channel opening mediates the secretion of nitric oxide and ROS (see
above), which in turn affect the outcome of ischemic damage (406) and may mediate the protective effects of late
preconditioning (778), the role of these channels in cardioprotection and the genesis of preconditioning has largely
not been investigated. Likewise, the potential role(s) of
smooth muscle KATP channels to regulate blood flow, KATP
D) IS IT THE MITOCHONDRIAL OR THE SARCOLEMMAL
NEL THAT IS RESPONSIBLE FOR CARDIOPROTECTION?
channels in the specialized conduction system and their contribution to arrhythmogenesis, and atrial KATP channels
with their role in regulating ANP release, will all remain
largely unexplored until suitable tools become available to
investigate these questions.
8. Mechanisms by which KATP channels protect
against ischemic damage
A) THE ENERGY-SPARING HYPOTHESIS. KATP channel opening accelerates the time to contractile failure during ischemia, in
part due to enhancing action potential shortening, which in
turn leads to reduced Ca2⫹ influx into cells and a negative
inotropic effect (FIGURE 12). The decreased rate of ATP
consumption is expected to preserve intracellular nucleotide levels, thus having an anti-ischemic effect. This “ATPsparing hypothesis” has been postulated in Noma=s patchclamp study, in which the cardiac KATP channel was initially identified (607). Each of the steps in this protective
pathway has now been realized to some extent. Indeed,
contractile failure during ischemia is accelerated by KCOs
and mitigated by KATP channel blockers (556). Moreover,
KATP channel activation during ischemia mitigates Ca2⫹
overload (142, 480, 764), preserves mitochondrial integrity
(764) and leads to energy preservation (556) (see below).
B) PROTECTION OF MITOCHONDRIAL INTEGRITY.
Preconditioning
and KATP channel opening slows energy metabolism and
protects mitochondrial integrity during ischemia (196, 245,
264, 796, 887). This protection may potentially occur directly as a result of the activity of mitochondrial KATP chan-
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Rabbit
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Smooth muscle
Endothelium
Mitochondria
Uncoupling
KATP channels
KATP channels
mKATP channels
Energetics
Cardioprotection
KATP channels
Blood glucose?
NE/Ach?
KATP channels
Ca2+ overload
Neurons
Mitochondrial function
KATP channels
nels (611). This idea is that the K⫹ uptake into mitochondria during ischemia, together with the activity of a K⫹/H⫹
antiporter, better maintains matrix volume regulation,
which in turn stimulates the rate of oxidative phosphorylation (257) (FIGURE 12). Although this paradigm remains to
be proven in the setting of the ischemic heart, mitochondria
isolated from preconditioned hearts do have an elevated
rate of ATP synthesis (245). Curiously, in the latter study,
although 5-HD partially reversed the ATP synthesis rate,
diazoxide or HMR-1098 (when applied before ischemia)
did not stimulate the rate of ATP synthesis. KATP channel
openers such as diazoxide may have additional energetic
benefits. For example, in perfused rat hearts, diazoxide was
found to reduce cellular and mitochondrial ATPase activities, along with nucleotide degradation, which may contribute myocardial ATP preservation during ischemia (196).
Furthermore, proteomic analysis of diazoxide “preconditioned” rabbit ventricular myocytes showed a remarkable
plasticity in the expression and phosphorylation profiles of
proteins involved in mitochondrial energetics, including
subunits of tricarboxylic acid cycle enzymes and oxidative
phosphorylation complexes (20). The effects of these compounds, however, may be complex since KATP channel
openers such as diazoxide and pinacidil have opposite effects on mitochondrial respiration under different energetic
conditions (669). Mitochondrial integrity may also potentially be indirect in that sarcolemmal KATP channel opening
diminishes intracellular Ca2⫹ overload, which in turn may
protect mitochondrial function (764). KATP channel opening in the vasculature may also contribute to increase blood
flow to the ischemic tissue and thus to lessen the damaging
effects of ischemia.
C) OTHER MECHANISMS. During ischemia, reperfusion, and
ischemic preconditioning, a variety of mechanisms may
affect KATP channel function, and thereby directly or
224
indirectly contribute to the role of KATP channels during
these events. Receptor and molecular signaling represents just one of these and will not be discussed in detail
since an excellent recent review exists on this subject
(806). In brief, the KATP channel can be regulated by
several signaling cascades, including cAMP-mediated
events. The effects of cAMP are either mediated by PKA
(59, 625, 728) or through a PKA-independent pathway
that is mediated by EPAC proteins (420). Although
cAMP has been studied in the setting of the ischemic
heart for many years (71, 201), the role of these signaling
cascades on KATP channel in the ischemic setting is not
well defined. Another signaling molecule, PKC, has a
prominent role by initiating protection in various forms
of IPC (514). Endogenous mediators (autacoids) of IPC,
such as adenosine, signals through PKC signaling pathways (279). The mechanisms by which PKC confers cardioprotection are elusive and may involve preservation of
mitochondrial function, ROS generation, and improved
cardiac overload (195, 895). Both mitochondrial and sarcolemmal KATP channels have been proposed as effectors
of PKC signaling (320, 436, 499, 503, 515, 752, 826,
861). The PKC family consists of 10 members, grouped
into classical (c), novel (n), and atypical classes (759).
The Ca2⫹-independent nPKC␧ isozyme (217) has a welldescribed protective role in ischemia/reperfusion and
ischemic preconditioning (369, 506, 759). The role of
nPKC␦ is controversial, since both protective and detrimental roles have been described (370, 551, 759). Interestingly, an increase in intracellular Ca2⫹ by itself can
mediate ischemic preconditioning (568), and there is
strong evidence that the protective effect is mediated by
activation of the Ca2⫹-dependent cPKC␣ isozyme (78,
333, 440, 617, 817, 893, 908, 923). KATP channels are
positively regulated by molecular signaling pathways relevant to IPC. Patch-clamp data demonstrate that PKC
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Heart
Pancreas
FIGURE 13. Different subtypes of KATP
channels may synergistically interact to protect the heart against stress and ischemic
insults. There has been much emphasis on
opening of mitochondrial and sarcolemmal
KATP channels within cardiac myocytes to
protect against stress responses. However, KATP channels in other tissues may
contribute, for example, to cause vasodilation by hyperpolarizing smooth muscle myocytes or participate in the release of vasoactive substances (such as nitric oxide) in
the endothelium. KATP channels in nonvascular cell types may further contribute, for
example, by regulating the release of neurotransmitters from cardiac neurons.
KATP CHANNELS IN CARDIOPROTECTION
The downstream effectors of the PKC pathway remain to be
fully identified and include AMPK (911), which has a demonstrated cardioprotective role in ischemia/reperfusion and
ischemic preconditioning (98, 101, 112, 367, 467, 751,
885, 912). AMPK may signal through multiple mechanisms, including an altered glucose metabolism (520) and
enhanced glucose uptake during ischemia (398, 677), which
is mediated by the translocation of the glucose transporter
GLUT4 from endosomes to the sarcolemma (471, 493,
604) and a reduction in GLUT4 endocytosis (894). A role
for KATP channels was demonstrated by the finding that
Kir6.2 knockout reversed the cardioprotection elicited by
AMPK activation (190). It appears that AMPK can affect
KATP channels in at least two ways: AMPK activation increases the open probability of ventricular KATP channels
(905), but also stimulates translocation of KATP channels to
the surface membrane; at least in pancreatic ␤-cells (109,
504, 632) (also see sect. VI). Studies with cellular models of
ischemic or pharmacological preconditioning have suggested that KATP channel translocation to the surface might
also be an important element of AMPK signaling in the
ischemic heart (767, 824). Although a functional role for
endosomal KATP channels has been suggested (47), trafficking of KATP channel as a protective mechanism during ischemic preconditioning in intact hearts has not been directly
investigated.
A myriad of other intracellular events and signaling cascades may potentially affect KATP channel synthesis, trafficking, function, and degradation during ischemia and
ischemic preconditioning. A few of these have started to
emerge in recent publications. For example, cGMP, which
has a known protective role in ischemic preconditioning
(517), has been shown to stimulate cardiac KATP channels
via a ROS/calmodulin/CaMKII signaling cascade (103).
Other studies, however, suggested a negative role for CaMKII activation in the regulation of KATP channel density by
phosphorylation of specific tyrosine residues in the Kir6.2
COOH terminus and potentially influencing its interaction
with the ␮2 subunit of the AP2 adaptor complex, and thus
promoting internalization (495, 741). Much research is
needed to elucidate the relevance of these findings in KATP
channel function and trafficking during cardiac ischemia
and IPC.
9. KATP channels in the coronary vasculature
Smooth muscle KATP channels have a widely acknowledged role in maintaining basal coronary vascular tone in
response to various physiological stimuli (see above).
They also have an established role for the increased blood
coronary flow in response to hypoxic conditions. The
involvement of KATP channels was first revealed when it
was found that glibenclamide blocks hypoxia-induced
vasodilation in coronary arteries (161). Thus stress
events that impair energy metabolism and intracellular
nucleotide concentrations appear to be sufficient to activate KATP channels in coronary arterioles, which in turn
causes membrane hyperpolarization decreased Ca2⫹
fluxes and vasodilation (83).
A) CORONARY BLOOD FLOW DURING ISCHEMIA. Myocardial ischemia most often originates from impaired blood flow. Even
in vessels not directly affected (e.g., by a blood clot), myocardial ischemia can severely compromise coronary vasodilation and blood flow, which has direct negative consequences for the fate of cardiac myocytes during ischemia/
reperfusion. It is therefore important to consider the
changes that ischemia may have on blood flow regulation.
The evidence for an involvement of KATP channels in postischemic coronary blood flow is scant. Ischemia has been
shown to induce rapid alterations in local myocardial blood
flow patterns (572), which impacts local perfusion. Myocardial hypoxia was suggested to be the major factor stimulating microvascular vasodilation of resistance vessels distal to the coronary artery stenosis (702), and it is likely that
hypoxia signals via KATP channel opening in the ischemic
setting.
B) REACTIVE HYPEREMIA.
In many organs, including the heart,
a brief period of ischemia is inevitably followed by a large
and transient increase in blood flow. This phenomenon,
called reactive hyperemia, is used as an index of coronary
flow reserve (129). KATP channels appear to have a key role
in the mechanism of coronary reactive hyperemia since glibenclamide inhibits the peak blood flow responses and the
duration of the hyperemic period in mouse, dog, guinea pig,
and human hearts (33, 46, 121, 192, 913). KATP channels in
both the coronary microvasculature and larger vessels are
involved in this response (453). Coronary microvascular
dysfunction results in a reduction of the flow reserve and a
failure of myocardial oxygen consumption to meet demand.
Although a role for KATP channels in the coronary smooth
muscle cells is easily postulated, it appears that the endothelium may also be involved since endothelium removal
reduces the vasodilatory response to KATP channel openers
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activates cardiac KATP channels directly (6, 364, 365,
384, 501, 823, 937) and upregulates KATP channel surface density (199, 824). Moreover, the Ca2⫹-dependent
and Ca2⫹-independent PKCs may act synergistically to
activate KATP channels (36, 384). It has also been shown
that specific PKC␧ activator (␺␧RACK) peptides (185)
prime KATP channels to open during simulated preconditioning in isolated cardiomyocytes. In smooth muscle,
however, Ca2⫹-mediated PKC activation may cause internalization of the KATP channels (36). A possible role
for PKC␦ (in concert with AMPK and p38) in regulating
the KATP channel surface density in ventricular myocytes
has been suggested (824). Apart from these studies, the
effects of different PKC isozymes on KATP channel function and trafficking during IPC have not been fully studied.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
Table 11. Cardiovascular phenotypes associated with genetic variation in KATP channel genes
Subunit/Gene
Kir6.1/KCNJ8
Known SNP
Frequency
Brugada syndrome
(OMIM: 601144) and
J-wave syndromes
c.1265C-T transition, resulting in a
S422L substitution. Mutant
channels have a gain of function.
The mutation was not
found in 1,200
control alleles
49, 143,
557
Ventricular fibrillation
with early
repolarization (OMIM:
613601)
c.1265C-T transition, resulting in a
S422L substitution
This variant was
absent in 764 alleles
from healthy
controls
308
Early repolarization of
the action potential
and atrial fibrillation
c.1265C-T transition, resulting in a
S422L substitution
The variant was absent
in 368 controls
175
Early infantile epileptic
encephalopathy
(OMIM: 614558)
c.1265C-T transition, resulting in a
S422L substitution
The variant was
identified in
16/3510 European
Americans, 1/1869
African Americans
and 4% of Ashkenazi
Jews
838
Hypertrichotic
osteochondrodysplasia
or Cantú syndrome
(OMIM: 239850)
De novo c.526T-A transversion,
resulting in a C176S substitution.
Mutant channels have a reduced
ATP sensitivity and gain of
function.
The mutation was
absent in 2,096 inhouse exomes, or in
6,503 exomes in
the NHLBI Exome
Variant Server
database
136
SUR2/ABCC9
Sudden infant death
syndrome
E332del and V346I mutation in the
COOH terminus
Heart failure
E23K amino acid substitution
88
Absent in 400 and
200 ethnic-matched
reference alleles
803
rs5219
the KK genotype,
present in 18% of
heart failure patients
664
Dilated cardiomyopathy
E23K and I337V polymorphisms
Dilated cardiomyopathy
10 CMD1O (OMIM:
608569)
G-to-A transition at nucleotide
4537 resulting in an A1513T
substitution.
rs121909304
This mutation was not
identified in 500
unrelated control
individuals
882
67
A 3-bp deletion followed by a 4-bp
insertion (45704572delTTAinsAAAT) causing a
frameshift at L1524 and
introducing 4 anomalous terminal
residues followed by a premature
stop codon.
None
This mutation was not
identified in 500
unrelated control
individuals
67
Atrial fibrillation, familial
12 (OMIM: 614050)
heterozygosity for a 4640 C to T
transition in exon 38 of the
ABCC9 gene, resulting in a
T1547I substitution in the COOH
terminus
rs387906805
This mutation was not
identified in 2,000
unrelated, healthy
and predominantly
white individuals
619
Hypertrichotic
osteochondrodysplasia
or Cantú syndrome
(OMIM: 239850)
3460C-T transition in exon 27,
resulting in an R1154W
substitution in TMD2
rs387907208
Not present in
⬎5,000 publicly
available exomes
324
3461G-A transition in exon 27,
resulting in an R1154Q
substitution in TMD2.
rs387907209
Not present in
⬎5,000 publicly
available exomes
324, 831
3128G-A transition, resulting in a
C1043Y substitution in TMD2.
rs387907210
Not present in
⬎5,000 publicly
available exomes
831
1433C-T transition, resulting in an
A478V substitution in TMD1.
rs387907211
Not present in
⬎5,000 publicly
available exomes
831
3347G-A transition, resulting in
R1116H substitution in TMD2.
Patch-clamp experiments
demonstrated a reduced ATP
sensitivity.
rs387907227
Not present in
⬎5,000 publicly
available exomes
324
3346C-T transition, resulting in an
R1116C substitution in TMD2.
rs387907228
Not present in
⬎5,000 publicly
available exomes
324
Continued
226
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Variant
c.193G-A transition, resulting in a
V65M substitution
Kir6.2/KCNJ11
Reference
Nos.
Disease
KATP CHANNELS IN CARDIOPROTECTION
Table 11.—Continued
Subunit/Gene
Disease
Variant
Known SNP
Frequency
Reference
Nos.
3058T-C transition, resulting in a
S1020P substitution in TMD2
rs387907229
Not present in
⬎5,000 publicly
available exomes
324
78C-T transition, resulting in a
H60Y substitution in TMD0
rs387907230
Not present in
⬎5,000 publicly
available exomes
324
Coronary spasm and
acute myocardial
infarction
V734I in the nucleotide binding
domain 1
rs61688134
0.007015 allele
frequency*
748
Brugada and early
repolarization
syndrome (OMIM:
601144)
V734I, E1784K, S1402C
rs61688134
0.007015 allele
frequency*
362
and the ischemic reactive hyperemic response in coronary
arteries in the instrumented dog heart (472). More work is
needed to investigate the contribution of different KATP
channels in the vascular bed and how (if at all) they relate to
other mechanisms of reactive hyperemia, such as nitric oxide production (453).
C) THE “NO REFLOW” PHENOMENON. A therapeutic goal during
reperfusion of previously ischemic tissue (e.g., following
angioplasty) is to restore blood flow as rapidly and effectively as possible. However, as initially described by Kloner
et al. (451), successful restoration of coronary flow does not
necessarily translate into improved tissue perfusion. This
“no reflow” phenomenon, which is responsible for poor
clinical prognosis (429, 430), is characterized by microvascular and endothelial dysfunction (561). Several studies
have implicated a role for KATP channels in the no-reflow
phenomenon. In a mini-swine model of regional ischemia,
simvastatin was found to limit the area of no-reflow after
ischemia/reperfusion, determined by myocardial contrast
echocardiography and histological evaluation (896). In this
study, postinfarction treatment with glibenclamide abrogated the protective effect of simvastatin, suggesting that
simvastatin reduced myocardial no-reflow by KATP channel
activation. In another mini-swine study, remote periconditioning (brief cycles of ischemia and reperfusion of a remote
organ applied during sustained myocardial ischemia) decreased the area of no-reflow in a glibenclamide-sensitive
manner, also suggesting an involvement of KATP channels
(926). No-reflow is also reduced by KATP channel openers,
angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta receptor blockers and adenosine, and
in each case the protection is lost by coadministration of
glibenclamide (924, 925, 927, 928). It is possible that at
least some of the protective effect may be mediated by modulating the production or release of vasoactive substances
(924, 925, 927). This is a potentially important and therapeutically relevant field of study and further mechanistic
studies are warranted.
C. Hypertension and Dilated
Cardiomyopathy
Congestive heart failure occurs when a mismatch exists between the ability of the heart to deliver blood and the needs
of the body. Common causes of heart failure include cardiac
insufficiency due (among others) to myocardial infarction
and high blood pressure, which in turn are caused by coronary atherosclerosis and kidney disorders. Although not a
direct cause of heart failure, experimental evidence suggests
that KATP channels may be involved. For example, in a dog
heart failure model with ventricular pacing, an elevation in
left atrial pressure was described. Concomitant with the
atrial stretch, plasma atrial natriuretic peptide (ANP) levels
and urinary sodium excretion were elevated (107). The release of ANP from atria is known to be modulated by KATP
channel opening (see sect. VIIB). Consistently, it was found
that the KATP channel blocker glibenclamide delayed the
increase in plasma ANP levels and decreased urinary Na⫹
excretion. These data point to a possible protective role for
atrial KATP channels in the compensatory release of atrial
ANP in response to an elevated blood pressure. The
Kir6.2⫺/⫺ mice have clarified a further role for KATP channels: in an experimental hypertension model consisting of a
combination of a left nephrectomy, long-term treatment
with deoxycorticosterone and a high-salt diet, the knockout
mice exhibited a decreased survival rate and these mice
more readily developed ventricular remodeling and heart
failure (419), associated with unfavorable proteomic remodeling as determined by mass spectrometry (943). Moreover, with pressure overload imposed on the left ventricle
by transverse aortic constriction, Kir6.2⫺/⫺ mice displayed
compromised myocardial performance with elevated left
ventricular end-diastolic pressure followed by biventricular
congestive heart failure. Glibenclamide could recapitulate
this phenotype in wild-type mice (890). Proteomic profiling
of KATP channel-deficient hypertensive heart maps risk for
maladaptive cardiomyopathic outcome. Combined, these
data suggest that KATP channels have a protective role in the
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OMIM, Online Mendelian Inheritance in Man database (http://omim.org). *http://exac.broadinstitute.org/.
MONIQUE N. FOSTER AND WILLIAM A. COETZEE
transition from conditions of imposed hemodynamic load
to the development of maladaptive pathological remodeling
and heart failure. The relationship between KATP channels
and the development of failure are not clear at present.
X. GENETIC VARIATION IN KATP CHANNEL
GENES: RELEVANCE TO
CARDIOVASCULAR DISEASE
Recent data demonstrate associations in genetic variation in KCNJ8 (Kir6.1) and ABCC9 (SUR2) with cardiovascular disease (TABLE 11). For example, genetic variation in KCNJ8 has been linked to risk of Brugada syndrome, J wave syndromes, ventricular fibrillation, atrial
fibrillation, and early infantile epileptic encephalopathy.
Interestingly, it is the same genetic variant, a c.1265C-T
transition that results in a S422L substitution in the
Kir6.1 COOH terminus, which is linked to all of these
conditions. While clearly important, it is not obvious
how this variant has such diverse phenotypes, especially
given that Kir6.1 is not generally thought of as a subunit
that gives rise to the ventricular KATP channel (TABLE 2).
Moreover, although the variant is present at low frequency in European Americans and African-American
individuals, it is present in up to 4% of Ashkenazi Jews
(838). Patch-clamp studies report that the S422L mutant
Kir6.1 channels have a gain of function due to a reduced
ATP sensitivity, thus resulting in incomplete closing of
the channel under normoxic conditions (49, 557). Recent
data also demonstrate a link between KCNJ8 genetic
variation and hypertrichotic osteochondrodysplasia, also
228
XI. CONCLUSIONS
It has been known for a long time that KATP channels are
expressed ubiquitously and that they have diverse functions in different cell types (24). In some cell types, such
as pancreatic ␤-cells, the physiological role(s) of KATP
channels are characterized better than others. Molecular
cloning of subunits of plasma/sarcolemmal KATP channels, the development of transgenic and knockout mice
targeting these subunits, and the relationship between
human disease and genetic variations in the genes coding
for these subunits are instrumental in reaching a more
complete understanding of the rich diversity of KATP
channels within components of the cardiovascular system (SA node, atria, specialized conduction system, ventricle, smooth muscle, and endothelium). Pharmacological approaches have been similarly helpful in underscoring the important roles of KATP channels in vascular and
cardiac function in cardiovascular pathologies, but these
approaches are limited due to the overlapping pharmacological profiles of most of these KATP channel modulating compounds and the fact that the effects of many of
these compounds are altered by the cellular metabolic
state. Molecular identification of each of the KATP channel types, particularly the mitochondrial KATP channel,
and the development of small molecules with better target selectivity, will be of enormous benefit in moving
forward the field. Undue emphasis on the functional and
pathophysiological role of any one of the KATP channels,
however, should be avoided since it is likely that the
various types of KATP channels in the different cardiovascular tissues synergistically interact to protect against
stress. It is even likely that KATP channels in noncardiovascular tissues, such as cardiac neurons, fibroblasts, and
macrophages, may help to shape the cardiovascular responses to stress by regulating the release of hormones
(ACh and NE) and being involved in inflammatory responses. It is hoped that future studies may find a way to
comprehensively investigate the diverse roles of KATP
channels in the cardiovascular system.
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Genetic variation and mutations in KATP channel subunit
genes have been linked to the etiology of a number of lifethreatening human diseases (136, 599, 620). A number of
mutations in KCNJ11 (Kir6.2) and ABCC8 (SUR1) have
been associated with insulin disorders, including permanent
neonatal diabetes (OMIM: 606176), transient neonatal diabetes (OMIM: 610582), familial hyperinsulinemic hypoglycemia (OMIM: 601820), and susceptibility to type 2
diabetes mellitus (OMIM: 125853). These will not be discussed, and the reader is referred to reviews on this subject
(238, 592). Mutations in these two genes are generally not
associated with cardiovascular disease. An exception is a
polymorphism that results in an E23K amino acid substitution in the Kir6.2 NH2 terminus. Homozygosity for K23
(the KK variant), which occurs more frequently in type II
diabetic than in control subjects (181, 319, 715), is also
overrepresented in individuals with dilated cardiomyopathy and congestive heart failure compared with controls,
and is also associated with abnormal exercise stress testing
(664). The K23 KK genotype was additionally associated
with greater left ventricular size among subjects with increased stress load due to hypertension, suggesting that the
Kir6.2 K23 polymorphism may be a risk factor for adverse
subclinical myocardial remodeling (665).
named Cantú syndrome (281, 599), in which hypertrichosis leads to thick scalp hair and other abnormalities.
Cardiac and vascular abnormalities occur in ⬃80% of
these cases and may include patent ductus arteriosus,
ventricular hypertrophy, pulmonary hypertension, pericardial effusions and tortuous retinal vessels, and multiple tortuous pulmonary arteriovenous communications
(281). Two KCNJ8 variants, resulting in Kir6.1 amino
acid substitutions V65M or C176S, have been linked to
this disorder. Several ABCC9 variants have also been
linked to Cantú syndrome, resulting in SUR2 amino acid
substitutions including H60Y, A478V, S1020P,
C1043Y, R1116H, R1116C, R1154W, and R1154Q (TABLE 11). SUR2 mutations (A1513T, early truncation at
L1524 and T1547I) have also been linked to dilated cardiomyopathy and familial atrial fibrillation.
KATP CHANNELS IN CARDIOPROTECTION
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence:
W. A. Coetzee, NYU School of Medicine, Alexandria Center for Life Science 824, 450 East 29th St., New York, NY
10016 (e-mail: [email protected]).
13. Alekseev AE, Hodgson DM, Karger AB, Park S, Zingman LV, Terzic A. ATP-sensitive
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15. Ammala C, Moorhouse A, Ashcroft FM. The sulphonylurea receptor confers diazoxide sensitivity on the inwardly rectifying K⫹ channel Kir6.1 expressed in human embryonic kidney cells. J Physiol 494: 709 –714, 1996.
GRANTS
This work was supported by National Institutes of Health
Grants HL085820, HL119209, and HL126905 and in part
by the New York Masonic Seventh District Association,
Inc.
No conflicts of interest, financial or otherwise, are declared
by the authors.
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