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

Abstract

Two-pore K (K) channels have been described in modulating background conductance as leak channels in different physiological systems. In the heart, the expression of K channels is heterogeneous with equivocation regarding their functional role. Our objective was to determine the K 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 channels in the heart. Comparing quantitative PCR expression of K channels between human heart tissue and iPSC-CMs revealed K1.1, K2.1, K5.1, and K17.1 to be higher expressed in cHVT, whereas K3.1 and K13.1 were higher in iPSC-CMs. Notably, K17.1 was significantly lower in niHF tissues compared with cHVT. Action potential recordings in iCells after K small interfering RNA knockdown revealed prolongations in action potential depolarization at 90% repolarization for K2.1, K3.1, K6.1, and K17.1. Here, we report the expression level of 10 human K 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 K17.1 as significantly reduced in niHF tissues and K4.1 as reduced in niHF compared with iHF. Thus, we advance the notion that K channels are emerging as novel players in cardiac ventricular electrophysiology that could also be remodeled in cardiac pathology and therefore contribute to arrhythmias. Two-pore K (K) channels are traditionally regarded as merely background leak channels in myriad physiological systems. Here, we describe the expression profile of K channels in human-induced pluripotent stem cell-derived cardiomyocytes and outline a salient role in cardiac repolarization and pathology for multiple K channels.

Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity

“…Additionally, Decher et al identified a mechanism in a patient whereby increased sodium permeability through a K 2p (TREK-1) predisposed the individual to right ventricular outflow tract ventricular tachycardia (34). Finally, recent work from our laboratory corroborates the notion that K 2p channels are more than simply background leak channels, acting as active participants in ventricular repolarization (35). Collectively, this evidence supports the idea that K 2p channels may modulate cardiomyocyte excitability and contribute to disease phenotypes as well as providing a therapeutic target.…”

Physiological and pathophysiological roles of the KCNK3 potassium channel in the pulmonary circulation and the heart

“…We showed that in the Kcnk3 deficient rat or with chronic pharmacological inhibition of KCNK3 with the compound A293 in healthy rats there was also increased heart rate compared to wild‐type or vehicle‐exposed rats, respectively (Lambert et al., 2018, 2019), confirming that KCNK3 function is essential for the control of heart rate. In human pluripotent stem cell‐derived cardiomyocytes, the knockdown of KCNK3 induced a significant prolongation of APD, confirming the contribution of KCNK3 in AP repolarization in human cardiomyocytes (Chai et al., 2017). In this way, KCNK3 appears to have an atrial‐specific expression in the human heart and generates electrical impulses.…”

Gene and Allele-Specific Expression Underlying the Electric Signal Divergence in African Weakly Electric Fish

“…Two-pore potassium channels ( K 2p ) usually generate an outward potassium current and are also known as potassium leak channels. When silencing the KCNK6 gene in the human heart, the action potential duration is prolongated ( Chai et al 2017 ). Another voltage-gated potassium channel gene KCNQ5 was decreasingly expressed in elongated EOD Campylomormyrus species.…”