Download ATP-sensitive potassium channels: metabolic sensing and

J Appl Physiol 103: 1888–1893, 2007;
doi:10.1152/japplphysiol.00747.2007.
Invited Review
HIGHLIGHTED TOPIC
Perspectives in Innate and Acquired Cardioprotection
ATP-sensitive potassium channels: metabolic sensing and cardioprotection
L. V. Zingman,1,2 A. E. Alekseev,2 D. M. Hodgson-Zingman,1 and A. Terzic2
1
University of Iowa, Carver College of Medicine, Iowa City, Iowa; and 2Mayo Clinic College of Medicine,
Rochester, Minnesota
homeostasis; energetics; heart failure; energetic signaling
bodily homeostasis, facilitating delivery of oxygen and nutrients, while assisting with
metabolic end-product removal. The cardiovascular system
operates under a variety of demands, ranging from conditions
of rest to extreme stress, the later requiring significant increase
in the amount of blood that needs to be pumped. Even a minor
mismatch between cardiac workload and organism needs can
precipitate a fatal outcome (9, 20, 44). Heart muscle itself is a
high-energy, demanding organ with ⬃2% of ATP content
consumed with every beat, primarily supporting excitationcontraction coupling and force generation. Without proper
adjustment of ATP production to match workload, energetic
resources would be rapidly consumed (⬃15 s to 1 min, depends on heart rate), underscoring the energy dependence of
the working myocardium (9, 44).
How the heart muscle matches the rates of ATP production
with utilization is an area of active investigation. Traditional
models of feedback adjustment of ATP hydrolysis and synthesis, based simply on cytosolic levels of ADP and inorganic
phosphate, are reevaluated, as no tight correlation between
cardiac workload and changes in bulk adenine nucleotide or
inorganic phosphate levels is readily demonstrable in vivo or
THE HEART FUNCTIONS TO MAINTAIN
Address for reprint requests and other correspondence: L. Zingman, Univ. of
Iowa, Dept. of Internal Medicine, 285 Newton Rd., CBRB2296, Iowa City, IA
52242 (e-mail: [email protected]).
1888
in vitro (4, 9, 20, 44, 59). This creates an apparent paradox
where, at maintained ATP concentrations, ATPases with a high
affinity toward ATP would function virtually in an independent
mode from energy stores. The explanation may lie in metabolic
compartmentation, metabolic “channeling”, cooperative kinetics, or parallel regulation of ATP-producing and -consuming
cellular systems (4, 9, 20, 31, 37, 44, 46, 53, 59). In this regard,
metabolic sensors, exemplified by the ATP-sensitive potassium
(KATP) channel, serve a critical role in the orchestration of cell
well-being (4, 33, 47, 58, 59, 69, 76, 78).
Formed as heteromultimers of inwardly-rectifying potassium K⫹ channel (Kir) 6.2 and ATP-binding cassette (ABC)
sulfonylurea receptor (SUR) 2A proteins, myocardial KATP
channels are unique channel-enzyme complexes that provide
linkage between cellular energetics and membrane excitability
(2– 4, 14, 26, 28 –30, 36, 43, 47, 54, 55, 58, 64, 70 –72, 75, 78).
KATP channels are coupled with phosphotransfer reactions that,
in cells in which the mobility of metabolites between intracellular microdomains is otherwise limited, integrate energetic
signaling systems (1, 4, 10, 11, 13, 15, 18, 19, 25, 59, 75).
Coupling of phosphotransfer pathways with KATP channels
permits a high-fidelity translation of energy fluxes into channel
gating, adjusting membrane excitability to match demand (1, 4,
13, 25, 33, 76). KATP channel-dependent modulation of cardiac
action potential duration, in accord with the cellular energetic
state, allows synchronized energy consumption and produc-
8750-7587/07 $8.00 Copyright © 2007 the American Physiological Society
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Zingman LV, Alekseev AE, Hodgson-Zingman DM, Terzic A. ATP-sensitive
potassium channels: metabolic sensing and cardioprotection. J Appl Physiol 103:
1888 –1893, 2007. doi:10.1152/japplphysiol.00747.2007.—The cardiovascular system operates under a wide scale of demands, ranging from conditions of rest to
extreme stress. How the heart muscle matches rates of ATP production with
utilization is an area of active investigation. ATP-sensitive potassium (KATP)
channels serve a critical role in the orchestration of myocardial energetic wellbeing. KATP channel heteromultimers consist of inwardly-rectifying K⫹ channel
6.2 and ATP-binding cassette sulfonylurea receptor 2A that translates local ATP/
ADP levels, set by ATPases and phosphotransfer reactions, to the channel pore
function. In cells in which the mobility of metabolites between intracellular
microdomains is limited, coupling of phosphotransfer pathways with KATP channels permits a high-fidelity transduction of nucleotide fluxes into changes in
membrane excitability, matching energy demands with metabolic resources. This
KATP channel-dependent optimization of cardiac action potential duration preserves
cellular energy balance at varying workloads. Mutations of KATP channels result in
disruption of the nucleotide signaling network and generate a stress-vulnerable
phenotype with excessive susceptibility to injury, development of cardiomyopathy,
and arrhythmia. Solving the mechanisms underlying the integration of KATP
channels into the cellular energy network will advance the understanding of
endogenous cardioprotection and the development of strategies for the management
of cardiovascular injury and disease progression.
Invited Review
KATP CHANNELS: METABOLIC SENSING AND CARDIOPROTECTION
Fig. 1. Schematic presentation of the ATP-sensitive potassium (KATP) channel’s role in the balance of cardiac ATP production and utilization. KATP
channels couple cardiac energetic load (set by heart rate arterial pressure and
action potential duration) and energy production through control of membrane
excitability. The homeostatic role of the KATP channel function is particularly
critical in conditions elevating cardiac workload: hypertension (HTN) and
tachycardia (THC).
J Appl Physiol • VOL
pore closure or negative channel gating (75). Recruitment of a
posthydrolytic MgADP-bound state promotes opening of ATPinhibited KATP channels or positive channel gating (75). Elevated levels of intracellular MgADP, as occurs under metabolic stress, effectively decelerate ATPase cycling, increasing
the probability of the posthydrolytic conformation associated
with channel opening. NBD2 ATPase catalysis is characterized
by a relatively long lifetime of the NBD2䡠ADP intermediate
state compared with shorter lifetimes in other intermediates,
NBD2䡠ATP and NBD2䡠ADP䡠Pi (10, 11, 75). Thus the probability that NBD2 will adopt the ADP-bound state through the
ATPase cycle will be higher than the probability that this state
will form through simple competitive binding in the absence of
ATPase activity (11, 59). An additional conformational rearrangement that transmits the information provided by catalytic
intermediates of SUR to the channel pore may rely on the
dimerization of the two NBDs, as recently established for a
number of ABC proteins (4, 5, 24, 27, 61). In the KATP channel
complex, cooperative interaction, rather than separate contributions of each of the NBDs in SUR2A, is critical for coupling
NBD2 ATP intermediates and the functional state of the KATP
channel pore (40 – 42, 68, 77).
KATP channels operate in a compartmentalized milieu with
diffusional restrictions. Intracellular bulk nucleotide levels have
apparently only limited direct effect on KATP channels (59). The
channel agonist, MgADP, even at saturating levels (⬎100 ␮M),
shifts the range for ATP-induced KATP channel inhibition to an
IC50 from ⬃30 to ⬃300 ␮M, which is below actual bulk intracellular ATP levels (6 –10 mM) and, therefore, cannot per se
explain promotion of channel activity (59). However, several
observations support the notion that energy consumption is
compartmentalized in cardiac cells and that the free diffusional
space within the cellular microenvironment is limited, thus
restricting metabolite mobility (4, 31, 37, 59). Thereby, in the
presence of local ATP-consuming systems, submembrane nucleotide concentrations will be distinct from average cytosolic
levels (59). This would provide a possible explanation for the
activity of KATP channels measured even in the absence of
detectable gross changes in cytosolic ATP/ADP levels. Although the existence of diffusional barriers may explain
KATP channel regulation by local nucleotide levels, their
function as cellular energetic sensors, securing beneficial
channel activity in accord with cellular energetic demand,
requires a network mechanism that would shunt diffusional
barriers, allowing cellular energetic signal transfer (18, 19,
46, 59).
KATP channels: components of the cellular energetic network. Nucleotide exchange between the SUR2A ATPase and
intracellular metabolic pathways provides a mechanism coupling KATP channel function with cellular energetics (10, 11,
75). Cardiomyocytes possess well-defined phosphotransfer
systems that facilitate energetic signaling between sites of ATP
production and ATP utilization or sensing (18, 19, 46, 50, 59).
Structural and functional interactions of KATP channel proteins
with the prototypic phosphotransfer enzymes, adenylate kinase
(AK; 2ADP 7 ATP ⫹ AMP) and creatine kinase (CK; ADP ⫹
CrP 7 ATP ⫹ Cr), are assured by the distribution of these
enzymes in distinct cellular compartments, including membranes, and their physical association with KATP channel subunits (1, 13, 18, 19). The high rate of the major phosphotransfer
reaction, catalyzed by CK, scavenges ATPase products and
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tion, preserving cellular energy balance at different workloads
(4, 76) (Fig. 1).
Cardiac KATP channels: Kir6.2/SUR2A complexes. Abundant in metabolically active tissues, KATP channels were originally discovered in the heart sarcolemma (48). Tetramers of
Kir6.2 comprise the pore of cardiac KATP channels (2, 14, 28,
36, 67). Yet pore-forming Kir6.2 subunits cannot readily traffic
to the plasma membrane alone, without the regulatory SUR
module, due to a COOH-terminal RKR endoplasmic reticulum
retention signal (56, 57, 74). Truncated Kir6.2, lacking retention signals, can reach the plasma membrane-generating channels that only partially reconstitute properties of intact KATP
channels (67). Both the NH2- and COOH-termini of Kir6.2
apparently contribute to recognition of ATP, the major inhibitory channel ligand, with two Kir6.2 subunits implicated in the
coordination of one ATP molecule (6, 63, 66). Mutations that
impact the ATP responsiveness of Kir6.2 alter cardiac mechanical properties at rest and produce a poor myocardial response
to ischemic and metabolic challenge (51), while in noncardiac
tissues they are associated with disease states characterized by
deficient metabolic coupling (21).
Assembly of Kir6.2 with SUR2A enhances ATP-induced
channel inhibition. Furthermore, fundamental KATP channel
properties, including stimulation by MgADP and potassium
channel openers, as well as inhibition by sulfonylurea drugs
that are absent in truncated Kir6.2 channels, are rescued by
coexpression of Kir6.2 with the SUR protein (4, 7, 12, 16,
28 –30, 43, 45, 50, 52, 60, 64). SUR2A, the regulatory subunit
of the cardiac KATP channel, incorporates two bundles of six
hydrophobic transmembrane-spanning domains (TMD) that
are fused to hydrophilic nucleotide binding domains (NBD),
also known as the ABCs (2, 4, 5, 8, 35, 40 – 42, 75). By virtue
of structure and sequence homology, SUR belongs to the
ABCC subfamily of ABC proteins (http://www.gene.ucl.ac.uk/
nomenclature/genefamily/abc.html) that usually exist as
dimers with two ABC modules and two TMDs (TMD-ABCTMD-ABC). SUR (TMD0-TMD-ABC-TMD-ABC) (4), in addition to its unique property of association with a distinct
protein subunit, Kir6.2, also contains an additional bundle of
five TMDs (TMD0), proposed to anchor SUR to the Kir6.2
channel pore (8). NBD2 of SUR, in the presence of Mg2⫹,
hydrolyses ATP, while NBD1 is primarily responsible for
nucleotide binding (10, 11, 22, 40 – 42, 68, 75, 77). The
intrinsic SUR-mediated catalysis is involved in the regulation
of Kir6.2 pore gating (10, 11, 75) (Fig. 2). The SUR ATPase
trapped in the prehydrolytic MgATP-bound state translates into
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KATP CHANNELS: METABOLIC SENSING AND CARDIOPROTECTION
facilitates disengagement of posthydrolytic conformations,
promoting SUR ATPase cycling (10, 11, 59, 75). As a consequence of metabolic stress, a drop of CK flux compromises
ADP removal from ATPase sites and suspends the ATPase
cycle in a MgADP-bound state, producing channel opening, a
regulation absent in knockout mice lacking the major CK gene
M-CK (1, 10, 75). Analogously, AMP, the substrate for AK,
antagonizes ATP-induced KATP channel closure, an effect lost
in cardiomyocytes from mice lacking the primary AK1 isoform
(13). Thus phosphotransfer reactions are identified regulators
of KATP channel activity, providing a mechanism for coupling
channel behavior with the cellular energetic state.
J Appl Physiol • VOL
KATP channels and cardioprotection. Due to integration
with the cellular energetic network, KATP channels adjust
cardiomyocyte membrane excitability and produce shortening of the cardiac action potential duration, limiting intracellular calcium loading under conditions of increased demand and high-cardiac performance. KATP channel-dependent action potential shortening secures electrical stability
and diastolic interval prolongation, preserving a systolic/
diastolic calcium differential that is optimal for cardiac
relaxation and suppression of triggered arrhythmia secondary to calcium-dependent afterdepolarizations (23, 25, 32–
34, 38, 49, 58, 73, 76).
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Fig. 2. Mutations in the ABCC9-encoded regulatory channel subunit sulfonylurea receptor (SUR) 2A disrupt KATP channel integration with cellular energetic
network. A: Lineweaver-Burk plot for nucleotide binding domain (NBD) 2 ATPase activities measured by spectrophotometry revealed a Vmax ⫽ 9.98 ⫾ 0.34
min⫺1 and Km ⫽ 0.11 ⫾ 0.02 mM, determined at 0 ADP plus creatine kinase (CK; 0.01 U/ml) and creatine phosphate (CrP; 5 mM). B: Lineweaver-Burk plot
for ADP-dependent inhibition of the NBD2 ATPase revealed KADP ⫽ 8.6 ⫾ 0.3 ␮M (5). C: CK (⫹ CrP) promotes ATP hydrolysis in a fusion NBD2-maltose
binding protein (MBP) constructs. Generation of [32P]Pi by purified constructs from [␥-32P]ATP was analyzed by thin-layer chromatography, followed by
autoradiography (10). D: rate-limiting steps in the SUR2A ATPase cycle are as follows: for wild-type (WT)-ADP dissociation (k4), for constructs repeating
SUR2A human mutations associated with dilated cardiomyopathy/Fs1524-Pi dissociation (k3), and for A1513T-abnormally slow k4. In addition, A1513T displays
the lowest k04 rate constant defining ADP association (11). E: ADP-scavenging by CK accelerates the ATPase in WT, but not in NBD2 mutants. F-G: Fs1524
and A1513T SUR2A mutants produced KATP channel phenotype characterized by reduced ATP sensitivity and blunted response to ADP relative to KATP channel
activity at zero nucleotide levels. [Adapted from Refs. 11 and 75.]
Invited Review
KATP CHANNELS: METABOLIC SENSING AND CARDIOPROTECTION
J Appl Physiol • VOL
missense and frame-shift mutations were mapped to domains
bordering the catalytic ATPase pocket within SUR2A. Mutant
SUR2A proteins reduced the intrinsic channel ATPase activity,
altering reaction kinetics and translating into a dysfunctional
channel phenotype with impaired metabolic signal decoding
and processing capabilities. These data implicate a link between mutations in the cardioprotective KATP channel and
susceptibility to myopathic disease and electrical instability.
Dilated cardiomyopathy with ventricular tachycardia due to
ABCC9 KATP channel mutations has been designated CMD10
(Online Mendelian Inheritance in Man no. 608569) to distinguish this entity from other etiologies causing this heterogeneous condition. The ultimate phenotype in the Kir6.2 knockout, under pressure overload, is development of heart failure
with cardiac chamber dilation, a phenotype similar to that
observed in patients with mutations in KATP channel genes (34,
73). Even in the absence of genetic deficit in KATP channel
proteins, cardiomyocytes in heart failure undergo extensive
remodeling, including diminished mitochondrial respiration,
suppressed CK flux, decreased energy storage, and cytoskeletal
disruption, although bulk cytosolic ATP levels are preserved
(4, 11, 25, 33). These changes impact metabolic signal generation, transduction, and decoding by KATP channels. KATP
channels from failing hearts display an improper response to
ATP and creatine kinase, a reduced recognition of metabolic
distress, and do not provide for appropriate action potential
shortening upon exposure to hypoxia (25). Consequently, such
hearts are excessively vulnerable to calcium loading and myocyte necrosis under stress that can be largely ameliorated by
pharmacological restoration of KATP channel opening with KATP
channel-opening drugs, such as nicorandil and pinacidil (25).
More recently, a KATP channel mutation conferring risk for
adrenergic atrial fibrillation originating from vein of Marshall
was identified (49). The vein of Marshall, a remnant of the left
superior vena cava rich in sympathetic fibers, is a recognized
source for adrenergic atrial fibrillation. Genetic investigation
uncovered a missense mutation (T1547I) also in the ABCC9
gene, encoding the SUR2A regulatory subunit of cardiac KATP
channels. Structural modeling of mutant KATP channels predicted,
and patch-clamp electrophysiology demonstrated, compromised
function with defective stress responsiveness. Targeted knockout
of the KATP channel verified the pathogenic link between channel
dysfunction and predisposition to adrenergic atrial fibrillation. In
this first report of genetic susceptibility to adrenergic vein of
Marshall atrial fibrillation, radiofrequency ablation was curative,
disrupting the gene-environment substrate for arrhythmia conferred by KATP channelopathy (49).
Thus cardiac KATP channels through tight integration with
cellular metabolic signaling pathways respond with high fidelity to perturbations in cellular energetics. This highly responsive integrated system adapts metabolic expenditures to available resources, resulting in an effective feedback that maintains
cellular well-being under a range of physiological and pathological conditions. Further understanding of mechanisms responsible for KATP channel regulation and KATP channelopathy-associated disease susceptibility provides novel insights
into endogenous cardioprotection and the development of strategies for the management of cardiovascular injury and disease
progression.
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KATP channel function is recognized as vital for adaptation
to physiological and pathological stress. Hearts genetically
deprived of KATP channels lack stress-induced cardiac action
potential shortening upon adrenergic stress (76). Indeed, loss of
this regulator of membrane electrical stability in the Kir6.2knockout predisposes to cytosolic calcium overload associated
with development of progressive contractile dysfunction and
death under acute stress (76). On autopsy, contraction bands,
pathognomonic of cytosolic calcium loading, are visible
throughout the myocardium of the Kir6.2-knockout, but not
wild-type, in response to ␤-adrenergic stress (76). Similarly,
under chronic stress associated with physical exertion, KATP
channel knockout compromises the benefit of exercise training,
resulting in cardiac functional and structural deficits (32). Thus
cardiac KATP channels, harnessing the ability to recognize
alterations in the metabolic state of the cell and translate this
information into changes in membrane excitability, provide a
link necessary for the maintenance of myocardial well-being
under stress-induced energy-demanding augmentation in performance.
In pathological conditions, KATP channels are recognized to
also serve a vital cardioprotective role. Genetic disruption of
KATP channels results in poor recovery following coronary
hypoperfusion and compromises the protective benefits of
ischemic preconditioning (23, 47, 58, 62), while overexpression of channel subunits generates a phenotype resistant to
ischemia (17). Analogous to ischemic preconditioning, pharmacological activation of the channel through use of KATP
channel openers displays cardioprotective outcome in hearts
subject to ischemic challenge (23, 33, 58, 62). This pharmacological preconditioning is abolished in the absence of Kir6.2containing KATP channels (23, 33, 58, 62). In fact, Kir6.2
knockout also negates protection afforded by ischemic preconditioning on myocardial energy generation, transfer, and utilization.
Total ATP turnover, a global parameter of myocardial energetic
dynamics, fails to increase in the ischemic-preconditioned KATP
channel knockout, as opposed to wild type, correlating with the
failure of preconditioned hearts lacking KATP channels to functionally recover (23). As discussed above, the maintenance of
energetic stability in the myocardium requires synchronized
ATP generation and utilization accomplished through energetic
phosphotransfer relay systems transferring energy from sites of
production to sites of utilization and promptly removing end
products from sites of utilization. In this regard, in wild-type
but not Kir6.2-knockout ischemic hearts, preconditioning preserves CK phosphotransfer, the major energy transfer pathway
in the heart (23, 33). Disruption of KATP channel function
forms the basis for reduction in energetic production and/or
consumption that contributes to contractile dysfunction. These
findings may provide a mechanistic basis for the potentially
deleterious outcomes associated with use of KATP channel
blockers, sulfonylurea medication, in the setting of myocardial
infarction (33).
Defects in the function of KATP channel proteins themselves,
disruption of intracellular metabolic networks, and/or disturbed
communication between channel proteins and the energetic
network can all contribute to susceptibility toward cardiac
disease and poor outcome (11, 49). In humans, mutations in the
ABCC9-encoded regulatory channel subunit SUR2A have been
demonstrated in a subset of patients with dilated cardiomyopathy and ventricular arrhythmia (11) (Fig. 2). The identified
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