The Susceptibilities of Human Ether-à-Go-Go-Related Gene Channel with the G487R Mutation to Arrhythmogenic Factors

• Published in: Biological & pharmaceutical bulletin Vol. 38; no. 5; pp. 781 - 784
• Main Authors: Hisajima, Nozomi, Hata, Yukiko, Kinoshita, Koshi, Fukushima, Toshiki, Nishida, Naoki, Kano, Masanobu, Tabata, Toshihide
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-05-2015; Japan Science and Technology Agency
• Subjects: Action Potentials - drug effects; Anti-Arrhythmia Agents - adverse effects; arrhythmia; Arrhythmias, Cardiac - etiology; Arrhythmias, Cardiac - genetics; Brugada Syndrome; Cardiac Conduction System Disease; class III antiarrhythmic drug; Ether-A-Go-Go Potassium Channels - genetics; Genotype; Heart - drug effects; Heart - physiopathology; Heart Conduction System - abnormalities; HEK293 Cells; Humans; Hypokalemia - complications; Ion Channel Gating - genetics; KCNH2; Kinetics; Kv11.1; Long QT Syndrome - etiology; Long QT Syndrome - genetics; Mutation; Patch-Clamp Techniques; pharmacogenomic; Phenethylamines - adverse effects; Phenotype; Potassium - metabolism; Potassium Channel Blockers - adverse effects; single-nucleotide polymorphism; Sulfonamides - adverse effects
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b14-00630

The human ether-à-go-go-related gene (hERG) channel mediates the rapid delayed rectifier potassium current (IKr) responsible for shaping the repolarization phase of cardiac action potentials. hERG mutation may cause hERG channel malfunction, leading to long QT syndrome and other arrhythmic disorders. Elucidation of the genotype–phenotype relationships of individual hERG mutations is key to the development of treatment for such arrhythmic disorders. We previously identified hERG(G487R), a missense mutant with a glycine-to-arginine substitution at position 487. In the absence of arrhythmogenic factors, hERG(G487R) subunit-containing channels show normal surface expression and gating kinetics. However, it remains unknown whether the mutation exacerbates hERG channel malfunction induced by arrhythmogenic factors. Here we used a voltage-clamp technique to compare the effects of the major arrythmogenic factors on wild-type hERG [hERG(WT)] and hERG(G487R) channel currents (IhERG) in HEK-293T cells. The extent of IhERG blockade by the antiarrhythmic drug dofetilide or E4031 was not different between these channels. On the other hand, the extracellular K+ concentration ([K+]ex)-dependent changes in the rates of recovery from inactivation and deactivation of IhERG were rather less obvious for hERG(G487R) channel than for hERG(WT) channel. These findings suggest that the inheritance of hERG(G487R) does not increase the risk of arrhythmic disorders induced by antiarrhythmic drugs or hypokalemia.