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• W1937577088 abstract "Editorial FocusNew insights into the complex effects of KChIP2 on calcium transientsValeria Mezzano and Gregory E. MorleyValeria MezzanoLeon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York and Gregory E. MorleyLeon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New YorkPublished Online:15 Aug 2015https://doi.org/10.1152/ajpheart.00511.2015This is the final version - click for previous versionMoreSectionsPDF (38 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat the initial phase of cardiac repolarization (phase 1 in humans) is mediated by the transient outward K+ current (Ito). Ito is composed of the Ca2+-independent K+ current (Ito1) and a Ca2+-activated chloride current (Ito2), both of which are voltage dependent (3). Ito1 is further subdivided into fast (Ito,f) and slow (Ito,s) (3). Ito,f is mediated by Kv4 channels that form complexes with K+ channel-interacting protein 2 (KChIP2) proteins in the majority of cardiomyocytes. Kv4 is the pore-forming unit, and KChIP2 is an accessory K+ channel-interacting protein residing on the cytoplasmic side (10, 12). The discovery of KChIP2 proteins in neurons (1) led to the generation of knockout mouse models of KChIP2 to study the role of this protein in cardiac electrophysiology through loss of function (9). Removal of KChIP2 in mice leads to disappearance of Ito,f. More recently, it was discovered that KChIP2 proteins also bind to Cav1.2, which is responsible for the L-type Ca2+ current (ICa,L) (15). In KChIP2−/− mouse cardiomyocytes, ICa,L is reduced but Cav1.2 protein levels are unchanged (15). Therefore, KChIP2 proteins are capable of modulating various ionic currents that determine the action potential plateau and regulate contractility.Action potential duration (APD) prolongation is widely reported to occur in many forms of heart failure. A reduction in Ito has been suggested to be a main contributing factor responsible for the prolongation of APD. KChIP2 expression has been also reported to be significantly reduced in human and animal models of cardiac hypertrophy and heart failure. Changes in KChIP2 expression have been reported to increase the trafficking of Ito channels to the cell membrane and shift the voltage dependence of activation to more negative values. The net result of these changes indicates that KChIP2 can modulate the amplitude of Ito more than eightfold. On the other hand, studies that have been designed to determine the ability of Ito to modulate APD have been somewhat conflicting. Depending on ICa,L levels, decreases in Ito can result in either increased or decreased APD (16). While other studies have reported increases in Ito have little or no effect on APD (11). Changes in Ito that occur with cardiac disease are often accompanied by changes in ICa,L. One potential explanation for the varied effects of Ito on APD could be related to complex interactions of these currents where the net effect on APD can vary. It is also possible that KChiP2 interactions with the channels responsible for Ito and ICa,L contribute to the net effects on cardiac function and APD.In a study by Grubb and colleagues (5) the role of KChIP2 in determining cardiomyocyte Ca2+ transients and how this affects cardiac function were investigated. Specifically, the study focused on finding the mechanisms responsible for the maintenance of cardiac function in the absence of KChIP2, given that both Ito,f and ICa,L are reduced. The authors confirmed previous reports that cardiac function is unchanged in KChIP2 knockout mice (9, 13) and that absence of KChIP2 in isolated myocytes decreased the peak inward Ca2+ current without changing the expression levels of the protein or kinetics responsible for ICa,L (15). Given that reduction in ICa,L might lead to decreased intracellular Ca2+ concentration transients and decreased contraction (7), the authors turned to computational and experimental studies to determine how KChIP2 deficiency might affect Ca2+-induced Ca2+-release (CICR). They addressed the role CICR by measuring synchronization between Ca2+ channels and ryanodine receptor (RyR) coupling, RyR sensitivity to Ca2+, sarcoplasmic reticulum Ca2+ load, fractional Ca2+ release, and rate of decay. Surprisingly none of those was decreased in KChIP−/− myocytes; furthermore, they report increased Ca2+ release with β-adrenergic stimulation, suggesting augmented sensitivity of the RyR. In view of these findings and on simulation data, the authors attribute preserved contractility to a prolongation in APD secondary to the loss of Ito,f. APD prolongation would provide sufficient time for intracellular Ca2+ concentration to rise in the presence of reduced ICa,L.Although this study provided new information on the effects of KChIP2 activity and Ca2+ transients, a few important issues worth mentioning remain unresolved. In particular, conflicting APD data have been reported in the KChIP2−/− mice. Initially it was reported that myocytes isolated from KChIP2−/− mice had increased APD (9). More recently, it was shown that differences in APD between isolated wild-type and KChIP2−/− myocytes were only observed at room temperature but not at physiological temperatures due to an increase in Ito,s (2, 9, 14). These results are in agreement with Thomsen et al. (14) who observed prolonged APD only in KChIP2−/− myocytes that had blocked Ito,s with 4-aminopyridine. In the current study, APD was measured at physiological temperature in isolated myocytes and was longer than wild-type controls. Microelectrode measurements obtained from the epicardial left ventricular surface of intact hearts were performed by Grubb et al. (6) in a previous study and were also prolonged in KChIP2−/− compared with wild-type mice. It remains to be determined if differences observed in KChIP2 effects on APD are due to a heterogeneity of the cardiomyocyte population being assessed. Another important issue is related to the proteins that interact with Kv4. Many other proteins have been found in ventricular tissue that coimmunoprecipitate with Kv4 and modulate either its localization at the membrane surface and/or its channel kinetics (10). Interestingly, these include Ca2+/calmodulin-dependent kinase 2 (CaMKII), which has been shown to have increased activity when Kv4 or KChiP2 are reduced (8). In this study, Grubb et al. report an increase in RyR sensitivity to β-adrenergic stimulation, which remains unexplained. One possible explanation might be the increased CaMKII activity, given that it has recently been shown that CaMKII increases RyR sensitivity to β-adrenergic stimulation (4). Finally, another component of CICR that might be involved in Ca2+ handling in pathological hearts and might influence RyR Ca2+ release is the Na+-Ca2+ exchanger (NCX). NCX influences [Ca2+] in the dyadic cleft, and it has been proposed that at highly positive membrane potentials NCX and ICa,L might act synergistically to trigger Ca2+ release (7). Overall the Grubb et al. study provides us with important information on the role of KChIP2 in modulating Ca2+ transients. In addition, these data help to emphasize the complex interactions between electrophysiological changes and their effects on cardiac function.GRANTSThis work was supported by National Heart, Lung, and Blood Institute Grant HL-076751 (to G. E. Morley).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).AUTHOR CONTRIBUTIONSV.M. and G.E.M. drafted manuscript; V.M. and G.E.M. edited and revised manuscript; V.M. and G.E.M. approved final version of manuscript.REFERENCES1. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ. Modulation of A-type potassium channels by a family of calcium sensors. Nature 403: 553–556, 2000.Crossref | PubMed | ISI | Google Scholar2. Foeger NC, Wang W, Mellor RL, Nerbonne JM. Stabilization of Kv4 protein by the accessory K+ channel interacting protein 2 (KChIP2) subunit is required for the generation of native myocardial fast transient outward K+ currents. J Physiol 591: 4149–4166, 2013.Crossref | PubMed | ISI | Google Scholar3. Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol 2: 185–194, 2009.Crossref | PubMed | ISI | Google Scholar4. Grimm M, Ling H, Pereira L, Willeford A, Gray CB, Erickson JR, Sarma S, Respress JL, Wehrens XH, Bers DM, Brown JH. CaMKIIdelta mediates beta-adrenergic effects on RyR2 phosphorylation and SR Ca leak and the pathophysiological response to chronic beta-adrenergic stimulation. J Mol Cell Cardiol 85: 282–291, 2015.Crossref | PubMed | ISI | Google Scholar5. Grubb S, Aistrup GL, Koivumaki J, Speerschneider T, Gottlieb LA, Mutsaers NA, Olesen SP, Calloe K, Thomsen MB. Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2. Am J Physiol Heart Circ Physiol 309: 481–489, 2015.Link | ISI | Google Scholar6. Grubb S, Speerschneider T, Occhipinti D, Fiset C, Olesen SP, Thomsen MB, Calloe K. Loss of K+ currents in heart failure is accentuated in KChIP2 deficient mice. J Cardiovasc Electrophysiol 25: 896–904, 2014.Crossref | PubMed | ISI | Google Scholar7. Heinzel FR, MacQuaide N, Biesmans L, Sipido K. Dyssynchrony of Ca2+ release from the sarcoplasmic reticulum as subcellular mechanism of cardiac contractile dysfunction. J Mol Cell Cardiol 50: 390–400, 2011.Crossref | PubMed | ISI | Google Scholar8. Keskanokwong T, Lim HJ, Zhang P, Cheng J, Xu L, Lai D, Wang Y. Dynamic Kv4.3-CaMKII unit in heart: an intrinsic negative regulator for CaMKII activation. Eur Heart J 32: 305–315, 2011.Crossref | PubMed | ISI | Google Scholar9. Kuo HC, Cheng CF, Clark RB, Lin JJ, Lin JL, Hoshijima M, Nguyen-Tran VT, Gu Y, Ikeda Y, Chu PH, Ross J, Giles WR, Chien KR. A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell 107: 801–813, 2001.Crossref | PubMed | ISI | Google Scholar10. Niwa N, Nerbonne JM. Molecular determinants of cardiac transient outward potassium current (Ito) expression and regulation. J Mol Cell Cardiol 48: 12–25, 2010.Crossref | PubMed | ISI | Google Scholar11. Schreieck J, Wang Y, Overbeck M, Schomig A, Schmitt C. Altered transient outward current in human atrial myocytes of patients with reduced left ventricular function. J Cardiovasc Electrophysiol 11: 180–192, 2000.Crossref | PubMed | ISI | Google Scholar12. Schultz JH, Janzen C, Volk T, Ehmke H. Kv4.2 and KChIP2 transcription in individual cardiomyocytes from the rat left ventricular free wall. J Mol Cell Cardiol 39: 269–275, 2005.Crossref | PubMed | ISI | Google Scholar13. Speerschneider T, Grubb S, Metoska A, Olesen SP, Calloe K, Thomsen MB. Development of heart failure is independent of K+ channel-interacting protein 2 expression. J Physiol 591: 5923–5937, 2013.Crossref | PubMed | ISI | Google Scholar14. Thomsen MB, Sosunov EA, Anyukhovsky EP, Ozgen N, Boyden PA, Rosen MR. Deleting the accessory subunit KChIP2 results in loss of Ito,f and increased IK,slow that maintains normal action potential configuration. Heart Rhythm 6: 370–377, 2009.Crossref | PubMed | ISI | Google Scholar15. Thomsen MB, Wang C, Ozgen N, Wang HG, Rosen MR, Pitt GS. Accessory subunit KChIP2 modulates the cardiac L-type calcium current. Circ Res 104: 1382–1389, 2009.Crossref | PubMed | ISI | Google Scholar16. Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res 81: 512–525, 1997.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: G. E. Morley, NYU School of Medicine, 522 First Ave., Smilow Bldg., 8th Fl., New York, NY 10016 (e-mail: gregory.morley@nyumc.org). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 309Issue 4August 2015Pages H553-H554 Copyright & PermissionsCopyright © 2015 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00511.2015PubMed26163446History Published online 15 August 2015 Published in print 15 August 2015 Metrics" @default.
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