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HERG Channel (Dys)function Revealed by Dynamic Action Potential Clamp Technique

Authors
  • Géza Berecki
  • Jan G. Zegers
  • Arie O. Verkerk
  • Zahurul A. Bhuiyan
  • Berend de Jonge
  • Marieke W. Veldkamp
  • Ronald Wilders
  • Antoni C. G. van Ginneken
Publisher
The Biophysical Society
Publication Date
Oct 08, 2004
Source
PMC
Keywords
Disciplines
  • Biology
License
Unknown

Abstract

The human ether-a-go-go-related gene (HERG) encodes the rapid component of the cardiac delayed rectifier potassium current (IKr). Per-Arnt-Sim domain mutations of the HERG channel are linked to type 2 long-QT syndrome. We studied wild-type and/or type 2 long-QT syndrome-associated mutant (R56Q) HERG current (IHERG) in HEK-293 cells, at both 23 and 36°C. Conventional voltage-clamp analysis revealed mutation-induced changes in channel kinetics. To assess functional implication(s) of the mutation, we introduce the dynamic action potential clamp technique. In this study, we effectively replace the native IKr of a ventricular cell (either a human model cell or an isolated rabbit myocyte) with IHERG generated in a HEK-293 cell that is voltage-clamped by the free-running action potential of the ventricular cell. Action potential characteristics of the ventricular cells were effectively reproduced with wild-type IHERG, whereas the R56Q mutation caused a frequency-dependent increase of the action potential duration in accordance with the clinical phenotype. The dynamic action potential clamp approach also revealed a frequency-dependent transient wild-type IHERG component, which is absent with R56Q channels. This novel electrophysiological technique allows rapid and unambiguous determination of the effects of an ion channel mutation on the ventricular action potential and can serve as a new tool for investigating cardiac channelopathies.

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