Modification by KCNE1 variants of the hERG potassium channel response to premature stimulation and to pharmacological inhibition

Physiological Reports

Chunyun Du¹  Aziza El Harchi¹  Henggui Zhang² 

[1] School of Physiology and Pharmacology and Cardiovascular Research Laboratories, Medical Sciences Building, University of Bristol, Bristol, U.K.;Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, U.K.

关键词: Cardiac;    cisapride;    clarithromycin;    hERG;    KCNE1;    Long QT;    potassium channels;    QT interval;    quinidine;   

DOI  :  10.1002/phy2.175

来源: Wiley

【 摘 要 】

Abstract

human Ether-à-go-go-Related Gene (hERG) encodes the pore-forming subunit of cardiac rapid delayed rectifier K⁺ current (I_Kr) channels, which play important roles in ventricular repolarization, in protecting the myocardium from unwanted premature stimuli, and in drug-induced Long QT Syndrome (LQTS). KCNE1, a small transmembrane protein, can coassemble with hERG. However, it is not known how KCNE1 variants influence the channel's response to premature stimuli or if they influence the sensitivity of hERG to pharmacological inhibition. Accordingly, whole-cell patch-clamp measurements of hERG current (I_hERG) were made at 37°C from hERG channels coexpressed with either wild-type (WT) KCNE1 or with one of three KCNE1 variants (A8V, D76N, and D85N). Under both conventional voltage clamp and ventricular action potential (AP) clamp, the amplitude of I_hERG was smaller for A8V, D76N, and D85N KCNE1 + hERG than for WT KCNE1 + hERG. Using paired AP commands, with the second AP waveform applied at varying time intervals following the first to mimic premature ventricular excitation, the response of I_hERG carried by each KCNE1 variant was reduced compared to that with WT KCNE1 + hERG. The I_hERG blocking potency of the antiarrhythmic drug quinidine was similar between WT KCNE1 and the three KCNE1 variants. However, the I_hERG inhibitory potency of the antibiotic clarithromycin and of the prokinetic drug cisapride was altered by KCNE1 variants. These results demonstrate that naturally occurring KCNE1 variants can reduce the response of hERG channels to premature excitation and also alter the sensitivity of hERG channels to inhibition by some drugs linked to acquired LQTS.

【 授权许可】

CC BY   
© 2013 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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