Contribution of two-pore K⁺ channels to cardiac ventricular action potential revealed using human iPSC-derived cardiomyocytes

Abstract

Two-pore K⁺ (K_2p) channels have been described in modulating background conductance as leak channels in different physiological systems. In the heart, the expression of K_2p channels is heterogeneous with equivocation regarding their functional role. Our objective was to determine the K_2p expression 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 K_2p channels in the heart. Comparing quantitative PCR expression of K_2p channels between human heart tissue and iPSC-CMs revealed K_2p1.1, K_2p2.1, K_2p5.1, and K_2p17.1 to be higher expressed in cHVT, whereas K_2p3.1 and K_2p13.1 were higher in iPSC-CMs. Notably, K_2p17.1 was significantly lower in niHF tissues compared with cHVT. Action potential recordings in iCells after K_2p small interfering RNA knockdown revealed prolongations in action potential depolarization at 90% repolarization for K_2p2.1, K_2p3.1, K_2p6.1, and K_2p17.1. Here, we report the expression level of 10 human K_2p channels 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 K_2p17.1 as significantly reduced in niHF tissues and K_2p4.1 as reduced in niHF compared with iHF. Thus, we advance the notion that K_2p channels are emerging as novel players in cardiac ventricular electrophysiology that could also be remodeled in cardiac pathology and therefore contribute to arrhythmias.<b>NEW & NOTEWORTHY</b> Two-pore K⁺ (K_2p) channels are traditionally regarded as merely background leak channels in myriad physiological systems. Here, we describe the expression profile of K_2p channels in human-induced pluripotent stem cell-derived cardiomyocytes and outline a salient role in cardiac repolarization and pathology for multiple K_2p channels.