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

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  • Hisajima Nozomi
    Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama
  • Hata Yukiko
    Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama
  • Kinoshita Koshi
    Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama
  • Fukushima Toshiki
    Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama
  • Nishida Naoki
    Department of Legal Medicine, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama
  • Kano Masanobu
    Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo
  • Tabata Toshihide
    Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama

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

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Abstract

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.

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