Contribution of two-pore K+channels to cardiac ventricular action potential revealed using human iPSC-derived cardiomyocytes.
Two-pore K+(K2p) channels have been described in modulating background conductance as leak channels in different physiological systems. In the heart, the expression of K2pchannels is heterogeneous with equivocation regarding their functional role. Our objective was to determine the K2pexpression profile and their physiological and pathophysiological contribution to cardiac electrophysiology. Induced pluripotent stem cells (iPSCs) generated from humans were differentiated into cardiomyocytes (iPSC-CMs). mRNA was isolated from these cells, commercial iPSC-CM (iCells), control human heart ventricular tissue (cHVT), and ischemic (iHF) and nonischemic heart failure tissues (niHF). We detected 10 K2pchannels in the heart. Comparing quantitative PCR expression of K2pchannels between human heart tissue and iPSC-CMs revealed K2p1.1, K2p2.1, K2p5.1, and K2p17.1 to be higher expressed in cHVT, whereas K2p3.1 and K2p13.1 were higher in iPSC-CMs. Notably, K2p17.1 was significantly lower in niHF tissues compared with cHVT. Action potential recordings in iCells after K2psmall interfering RNA knockdown revealed prolongations in action potential depolarization at 90% repolarization for K2p2.1, K2p3.1, K2p6.1, and K2p17.1. Here, we report the expression level of 10 human K2pchannels in iPSC-CMs and how they compared with cHVT. Importantly, our functional electrophysiological data in human iPSC-CMs revealed a prominent role in cardiac ventricular repolarization for four of these channels. Finally, we also identified K2p17.1 as significantly reduced in niHF tissues and K2p4.1 as reduced in niHF compared with iHF. Thus, we advance the notion that K2pchannels are emerging as novel players in cardiac ventricular electrophysiology that could also be remodeled in cardiac pathology and therefore contribute to arrhythmias.NEW & NOTEWORTHYTwo-pore K+(K2p) channels are traditionally regarded as merely background leak channels in myriad physiological systems. Here, we describe the expression profile of K2pchannels in human-induced pluripotent stem cell-derived cardiomyocytes and outline a salient role in cardiac repolarization and pathology for multiple K2pchannels.
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.|Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
Sam
S
Chai
Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
Xiaoping
X
Wan
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.|Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
Drew M
DM
Nassal
Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
Haiyan
H
Liu
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio.
Christine S
CS
Moravec
Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
Angelina
A
Ramirez-Navarro
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio; isabelle.deschenes@case.edu.|Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; and.
Isabelle
http://orcid.org/0000-0002-1812-7267
I
Deschênes
D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D002460:Cell Line; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection
D024683:Potassium Channels, Tandem Pore Domain
action potential duration; cardiac repolarization; heart failure; induced pluripotent stem cell-derived cardiomyocytes; two-pore potassium channels