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Editorial
Novel Mechanism of Transient Outward Potassium
Channel Current Regulation in the Heart
Implications for Cardiac Electrophysiology in Health and Disease
Michael S. Bohnen, Vivek Iyer, Kevin J. Sampson, Robert S. Kass
T
he cardiac action potential (AP) results from the summation of ion channel activity that depolarizes and then
repolarizes the plasma membrane, allowing for contraction
and relaxation of the atrial and ventricular chambers. After
the initial depolarization, a brief repolarization event occurs
in human hearts that sets the critically important plateau phase
of the AP during which calcium enters the cytosol, leading to
contraction; alteration of the plateau predisposes to arrhythmia. The brief repolarization before the plateau phase results
from rapid activation of voltage-gated potassium channels
known collectively as transient-outward potassium channels.
The K+ efflux through these channels causes a transient outward current known as Ito.1
Article, see p 1655
Ito may be further subdivided into a fast component Ito,f and
a slow component Ito,s.2 Both Ito subtypes activate rapidly at
membrane voltages positive to −30 mV; the primary difference between them is the time to inactivation because Ito,f inactivates over tens of milliseconds, whereas Ito,s inactivates over
hundreds of milliseconds.3 Ito,f is comprised of pore forming
alpha subunits Kv4.2 and Kv4.3, encoded by the KCND2 and
KCND3 genes, respectively. The alpha subunit coassembles
with accessory subunits KChIP2 and DPP6 to form the functional channel.4
Ito,f is abundantly expressed throughout the human heart,
with a greater Ito,f current density present in the atria and
Purkinje fibers than in the ventricular myocardium.2 The regional differential expression of Ito,f within the human heart
contributes to the observed differences in the morphology
of AP waveforms throughout different cells in the heart. For
example, atrial myocytes, where Ito,f is large, have a more
triangular AP shape and repolarize faster than ventricular myocytes. The differences in AP morphology and duration serve
physiological roles (eg, the longer plateau phase duration in
the ventricles allows for a more prolonged and greater force
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Department of Pharmacology (M.S.B., K.J.S., R.S.K.),
and Department of Medicine (V.I.), College of Physicians & Surgeons,
Columbia University, NY.
Correspondence to Robert S. Kass, PhD, Department of Pharmacology,
College of Physicians & Surgeons, Columbia University, 630 W 168th
St, Rm 2–401, New York, NY 10032. E-mail [email protected]
(Circ Res. 2015;116:1633-1635.
DOI: 10.1161/CIRCRESAHA.115.306438.)
© 2015 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.115.306438
of contraction), and alterations to them can lead to a wide
variety of cardiac disease phenotypes. For Ito alone, studies
demonstrate a correlation between increased Ito and early-onset lone atrial fibrillation, Brugada syndrome, and idiopathic
ventricular fibrillation, whereas decreases in Ito have been
demonstrated in heart failure.2,5,6 The clinical phenotypes can
be tied to the regulation of ion channel subunit expression.
Gain-of-function mutations in KCND3 give rise to early-onset
lone atrial fibrillation, whereas there is a relatively consistent
decrease in Ito because of reduction in Kv4.3 expression in the
setting of heart failure and concomitant ventricular remodeling.7 Implicit in this discussion is the understanding that regulation of Ito subunit expression has functional consequences on
the AP waveforms of different regions of the heart.
The continued improvements in our understanding of the
molecular components of cardiac ion channels and posttranscriptional regulation of these components deepen our
understanding of the pathophysiology of cardiac arrhythmia.
Although specific mutations in the pore forming subunits of
Ito have been studied in patients with cardiac disease, a growing interest in the role of post-transcriptional and post-translational modifications of ion channels has evolved. Recent Ito
studies have explored the impact of microRNAs on protein
expression and channel phosphorylation on Ito current density,
which together highlight the importance of regulation of the Ito
channel in cardiac myocytes.2 In the study by Li et al8 in this
issue of Circulation Research, the authors illustrate, for the
first time, regulation of Ito by a cold-inducible RNA-binding
protein (CIRP).9
RNA-binding proteins act as important regulators of gene
expression.10 CIRP, which was first identified in murine germ
cells exposed to low temperatures, is constitutively expressed
in many bodily tissues, including the brain, testis, lung, and
heart.11 CIRP acts as an RNA chaperone and regulatory molecule, controlling cellular processes, such as RNA splicing,
initiation of translation, and aiding the assembly, disassembly,
and transport of proteins.12 In the setting of cell stressors, such
as cold and hypoxia, CIRP expression is upregulated.13 In the
setting of hemorrhagic shock and sepsis, overactivity of CIRP
causes overproduction of inflammatory cytokines, furthering
hemodynamic instability. Before the work by Li et al,8 the role
of CIRP in the heart was unclear.
Using CIRP-knockout rats, Li et al8 reveal that the absence of
CIRP results in a shortened rate-corrected QT (QTc) interval on
ECG and decreased AP duration, tightly linked to an increase in
Ito (Figure A). Moreover, the CIRP-knockout rats did not have
altered transcription of KCND2 or KCND3, but rather had
increased expression of Kv4.2 and Kv4.3 subunits, resulting in
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at Columbia University on December 22, 2015
1633
1634 Circulation Research May 8, 2015
A
Rat Ventricle
mRNA encoding Kv4.2/4.3
CIRP
Ito,f
Ventricle
20mV
K+
K+
10ms
Ito,f
Human AP Predictions
Control Ito
1.5x Ito
2x Ito
Atria
0mV
20mV
20mV
0mV
Control Ito
1.5x Ito
2x Ito
KChIP2
KChIP2
B
0mV
Kv 4.2/4.3
Kv 4.2/4.3
100ms
100ms
Figure. Computational modeling of impact of cold-inducible RNA-binding protein (CIRP) Ito downregulation in rat and human
cardiomyocytes. A, Schematic of CIRP regulation in the rat cardiomyocyte (left), where the absence of CIRP leads to greater Ito density
and a shortened action potential (AP) duration (right). B, Computational modeling of human AP waveforms in ventricular (left) and atrial
(right) myocytes reveals expected tissue-specific effects when increasing Ito current density.
an approximate doubling of Ito density in ventricular myocytes.
KChIP2 expression was unaffected, and expression of other key
ion channels was not altered in the CIRP-knockout rats. These
data suggest that CIRP selectively regulates KCND2 and KCND3
gene expression in rat heart by preventing excessive protein
expression of the corresponding Kv4.2 and Kv4.3 subunits.
This new finding adds to our understanding of the regulation
of cardiac ion channels and AP characteristics. Extrapolating
the result from the rat model to larger mammals will prove
interesting as alterations in Ito produce differing effects on
APs depending on the morphology of the AP.1 Computational
modeling, for example, predicts that in human ventricle, small
decreases in Ito increase AP duration slightly, whereas large
increases can shunt the AP and cause rapid repolarization
(Figure B). Modeling also predicts that this effect is altered
in the atria and conducting system where a less pronounced
spike-and-dome AP is the baseline. This diversity of effects
of altering Ito in different regions of the heart likely explains
the variety of cardiac disease phenotypes attributable to alterations in Ito.
Because Ito plays a significant role in generating the normal cardiac AP, pharmacological modulations, in addition to
naturally occurring modulation, are active topics of research.
One example, the experimental drug NS5806, increases peak
Ito currents and slows channel inactivation in canine ventricular myocytes and can recapitulate the Brugada Syndrome phenotype.14 Furthermore, in failing hearts in which a decrease
in Ito expression has been shown to occur and to contribute
to failure-induced AP prolongation, NS5806 has been shown
to rescue, at least in part, Ito expression,15,16 suggesting that
activation of Ito may serve in the treatment of heart failure.
This proof-of-concept that Ito may be pharmacologically manipulated for therapeutic benefit potentially extends to other
cardiac disease conditions wherein Ito imbalance occurs.
The discovery that CIRP regulates Ito expression brings
CIRP to the forefront of gene regulation and pharmacology
in Ito-dependent cardiovascular disease. CIRP may be actively
released from cells and a prior study developed neutralizing
antisera containing IgG directed against CIRP, which successfully blocked CIRP and improved survival outcomes of hemorrhagic and septic animals.17 This study suggests that CIRP
represents a potential novel therapeutic target and opens the
door for important questions to address: how does CIRP regulation impact the human heart? Does CIRP activity change
in specific pathophysiologic settings, such as ischemic heart
disease or heart failure? As for the interaction of CIRP with
Ito channel components, does CIRP normally interfere with
translation initiation of the alpha subunits Kv4.2 and Kv4.3 or
another post-transcriptional process? Does CIRP affect normal folding of Kv4.2/Kv4.3 or does CIRP increase disassembly rates of Kv4.2/Kv4.3? These important questions, brought
to the forefront by the article by Li et al,8 remain unanswered,
with the field open to uncovering how exactly CIRP regulates
Ito in health and in disease, and the therapeutic potential for
CIRP regulation in the human heart.
Sources of Funding
Supported by National Institute of Health 5R01 GM109762-02.
Disclosures
None.
References
1. Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization.
Physiol Rev. 2005;85:1205–1253. doi: 10.1152/physrev.00002.2005.
2. Schmitt N, Grunnet M, Olesen SP. Cardiac potassium channel subtypes:
new roles in repolarization and arrhythmia. Physiol Rev. 2014;94:609–
653. doi: 10.1152/physrev.00022.2013.
Downloaded from http://circres.ahajournals.org/ at Columbia University on December 22, 2015
Bohnen et al CIRP Modulation of Ito in the Heart 1635
3.Niwa N, Nerbonne JM. Molecular determinants of cardiac transient
outward potassium current (I(to)) expression and regulation. J Mol Cell
Cardiol. 2010;48:12–25. doi: 10.1016/j.yjmcc.2009.07.013.
4. Guo W, Li H, Aimond F, Johns DC, Rhodes KJ, Trimmer JS, Nerbonne
JM. Role of heteromultimers in the generation of myocardial transient
outward K+ currents. Circ Res. 2002;90:586–593.
5. Olesen MS, Refsgaard L, Holst AG, Larsen AP, Grubb S, Haunsø S,
Svendsen JH, Olesen SP, Schmitt N, Calloe K. A novel KCND3 gainof-function mutation associated with early-onset of persistent lone atrial
fibrillation. Cardiovasc Res. 2013;98:488–495. doi: 10.1093/cvr/cvt028.
6. Xiao L, Koopmann TT, Ördög B, et al. Unique cardiac Purkinje fiber
transient outward current β-subunit composition: a potential molecular
link to idiopathic ventricular fibrillation. Circ Res. 2013;112:1310–1322.
doi: 10.1161/CIRCRESAHA.112.300227.
7. Soltysinska E, Olesen SP, Christ T, Wettwer E, Varró A, Grunnet M,
Jespersen T. Transmural expression of ion channels and transporters in human nondiseased and end-stage failing hearts. Pflugers Arch.
2009;459:11–23. doi: 10.1007/s00424-009-0718-3.
8. Li J, Xie D, Huang J, Lv F, Shi D, Liu Y, Lin L, Geng L, Wu Y, Liang D,
Chen YH. Cold-inducible RNA-binding protein regulates cardiac repolarization by targeting transient outward potassium channels. Circ Res.
2015;116:1655–1659. doi: 10.1161/CIRCRESAHA.116.306287.
9. Ferreira JP, Santos M. Heart failure and atrial fibrillation: from basic
science to clinical practice. Int J Mol Sci. 2015;16:3133–3147. doi:
10.3390/ijms16023133.
10. Lunde BM, Moore C, Varani G. RNA-binding proteins: modular design for efficient function. Nat Rev Mol Cell Biol. 2007;8:479–490. doi:
10.1038/nrm2178.
11. Nishiyama H, Danno S, Kaneko Y, Itoh K, Yokoi H, Fukumoto M, Okuno
H, Millán JL, Matsuda T, Yoshida O, Fujita J. Decreased expression of
cold-inducible RNA-binding protein (CIRP) in male germ cells at elevated temperature. Am J Pathol. 1998;152:289–296.
12. Gualerzi CO, Giuliodori AM, Pon CL. Transcriptional and post-transcriptional control of cold-shock genes. J Mol Biol. 2003;331:527–539.
13. Lopez M, Meier D, Müller A, Franken P, Fujita J, Fontana A. Tumor
necrosis factor and transforming growth factor β regulate clock genes
by controlling the expression of the cold inducible RNA-binding protein (CIRBP). J Biol Chem. 2014;289:2736–2744. doi: 10.1074/jbc.
M113.508200.
14. Calloe K, Cordeiro JM, Di Diego JM, Hansen RS, Grunnet M, Olesen
SP, Antzelevitch C. A transient outward potassium current activator recapitulates the electrocardiographic manifestations of Brugada syndrome.
Cardiovasc Res. 2009;81:686–694. doi: 10.1093/cvr/cvn339.
15. Cordeiro JM, Calloe K, Moise NS, Kornreich B, Giannandrea D, Di
Diego JM, Olesen SP, Antzelevitch C. Physiological consequences of
transient outward K+ current activation during heart failure in the canine
left ventricle. J Mol Cell Cardiol. 2012;52:1291–1298. doi: 10.1016/j.
yjmcc.2012.03.001.
16.Kääb S, Dixon J, Duc J, Ashen D, Näbauer M, Beuckelmann DJ,
Steinbeck G, McKinnon D, Tomaselli GF. Molecular basis of transient
outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density.
Circulation. 1998;98:1383–1393.
17. Qiang X, Yang WL, Wu R, Zhou M, Jacob A, Dong W, Kuncewitch M, Ji
Y, Yang H, Wang H, Fujita J, Nicastro J, Coppa GF, Tracey KJ, Wang P.
Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med. 2013;19:1489–1495.
doi: 10.1038/nm.3368.
Key Words: Editorial
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arrhythmia
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cold-inducible RNA-binding protein
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Novel Mechanism of Transient Outward Potassium Channel Current Regulation in the
Heart: Implications for Cardiac Electrophysiology in Health and Disease
Michael S. Bohnen, Vivek Iyer, Kevin J. Sampson and Robert S. Kass
Circ Res. 2015;116:1633-1635
doi: 10.1161/CIRCRESAHA.115.306438
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