Suppression of the hERG potassium channel response to premature stimulation by reduction in extracellular potassium concentration.

Dario Melgari,Jules C Hancox,Chunyun Du,Yihong Zhang,Aziza El Harchi

doi:10.14814/phy2.12165

Abstract

Potassium channels encoded by human ether‐à‐go‐go‐related gene (hERG) mediate the cardiac rapid delayed rectifier K+ current (IKr), which participates in ventricular repolarization and has a protective role against unwanted premature stimuli late in repolarization and early in diastole. Ionic current carried by hERG channels (IhERG) is known to exhibit a paradoxical dependence on external potassium concentration ([K+]e), but effects of acute [K+]e changes on the response of IhERG to premature stimulation have not been characterized. Whole‐cell patch‐clamp measurements of hERG current were made at 37°C from hERG channels expressed in HEK293 cells. Under conventional voltage‐clamp, both wild‐type (WT) and S624A pore‐mutant IhERG during depolarization to +20 mV and subsequent repolarization to −40 mV were decreased when superfusate [K+]e was decreased from 4 to 1 mmol/L. When [K+]e was increased from 4 to 10 mmol/L, pulse current was increased and tail IhERG was decreased. Increasing [K+]e produced a +10 mV shift in voltage‐dependent inactivation of WT IhERG and slowed inactivation time course, while lowering [K+]e from 4 to 1 mmol/L produced little change in inactivation voltage dependence, but accelerated inactivation time course. Under action potential (AP) voltage‐clamp, lowering [K+]e reduced the amplitude of IhERG during the AP and suppressed the maximal IhERG response to premature stimuli. Raising [K+]e increased IhERG early during the AP and augmented the IhERG response to premature stimuli. Our results are suggestive that during hypokalemia not only is the contribution of IKr to ventricular repolarization reduced but its ability to protect against unwanted premature stimuli also becomes impaired.

Highlights

Repolarization of cardiac action potentials (APs) depends on the interplay between inward and outward conductances during the AP plateau, with key roles identified for several potassium ion channels (Tamargo et al 2004). human ether-a-go-go-related gene (hERG) encodes a protein that underlies the pore-forming subunit of potassium channels mediating the rapid delayed rectifier current, IKr (Sanguinetti et al 1995; Trudeau et al 1995)
A paradoxical effect of altering [K+]e on IhERG amplitude was observed in early studies of IKr and hERG
The present results for WT IhERG recorded at 37°C from a mammalian cell expression system (Fig. 1) are in qualitative agreement with the findings of these earlier studies

Summary

Introduction

Repolarization of cardiac action potentials (APs) depends on the interplay between inward and outward conductances during the AP plateau, with key roles identified for several potassium ion channels (Tamargo et al 2004). hERG (human ether-a-go-go-related gene) encodes a protein that underlies the pore-forming subunit of potassium channels mediating the rapid delayed rectifier current, IKr (Sanguinetti et al 1995; Trudeau et al 1995). When hERG was initially identified, the magnitude of hERG current (IhERG) was demonstrated to have an anomalous dependence on extracellular K+ concentration ([K+]e), with low-[K+]e reducing outward IhERG amplitude and raised [K+]e augmenting the current (Sanguinetti et al 1995) These changes were the opposite of those expected due merely to changes in electrochemical gradient and were observed for native IKr (Sanguinetti and Jurkiewicz 1992; Yang and Roden 1996). This anomalous [K+]e dependence of IKr was subsequently proposed to arise from the rectification properties of the IKr channel and that rapid inactivation underlies this effect (Yang et al 1997), most likely because external K+ ions interact with the pore and influence the channel’s rapid collapse-of-pore type inactivation (Smith et al 1996). This property of IKr/hERG has clinical significance as, on the one hand, hypokalemia can exacerbate effects of QT interval prolonging, hERG-blocking drugs (Hancox et al 2008) whilst, on the other hand, potassium supplementation has been reported to improve repolarization in some LQT2 patients (Compton et al 1996; Etheridge et al 2003)

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