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

Physiological Reports

Dario Melgari¹  Chunyun Du¹  Aziza El Harchi¹  Yihong Zhang¹ 

[1] School of Physiology and Pharmacology and Cardiovascular Research Laboratories, University of Bristol, Bristol, UK

关键词: Human ether‐à‐go‐go‐related gene;    hyperkalemia;    hypokalemia;    long QT;    potassium;    potassium channels;    QT interval;   

DOI  :  10.14814/phy2.12165

来源: Wiley

【 摘 要 】

Abstract

Potassium channels encoded by human ether-à-go-go-related gene (hERG) mediate the cardiac rapid delayed rectifier K⁺ current (I_Kr), 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 (I_hERG) is known to exhibit a paradoxical dependence on external potassium concentration ([K⁺]_e), but effects of acute [K⁺]_e changes on the response of I_hERG 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 I_hERG 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 I_hERG was decreased. Increasing [K⁺]_e produced a +10 mV shift in voltage-dependent inactivation of WT I_hERG 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 I_hERG during the AP and suppressed the maximal I_hERG response to premature stimuli. Raising [K⁺]_e increased I_hERG early during the AP and augmented the I_hERG response to premature stimuli. Our results are suggestive that during hypokalemia not only is the contribution of I_Kr to ventricular repolarization reduced but its ability to protect against unwanted premature stimuli also becomes impaired.

【 授权许可】

CC BY   
© 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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