HERG channel (dys)function revealed by dynamic action potential clamp technique.

Details

Serval ID
serval:BIB_F99FF5F16896
Type
Article: article from journal or magazin.
Collection
Publications
Title
HERG channel (dys)function revealed by dynamic action potential clamp technique.
Journal
Biophysical journal
Author(s)
Berecki G., Zegers J.G., Verkerk A.O., Bhuiyan Z.A., de Jonge B., Veldkamp M.W., Wilders R., van Ginneken A.C.
ISSN
0006-3495 (Print)
ISSN-L
0006-3495
Publication state
Published
Issued date
01/2005
Peer-reviewed
Oui
Volume
88
Number
1
Pages
566-578
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The human ether-a-go-go-related gene (HERG) encodes the rapid component of the cardiac delayed rectifier potassium current (I(Kr)). 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 (I(HERG)) in HEK-293 cells, at both 23 and 36 degrees 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 I(Kr) of a ventricular cell (either a human model cell or an isolated rabbit myocyte) with I(HERG) 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 I(HERG), 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 I(HERG) 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.

Keywords
Action Potentials, Animals, Biophysics/methods, Cell Line, ERG1 Potassium Channel, Electrophysiology, Endocardium/metabolism, Ether-A-Go-Go Potassium Channels, Humans, Ion Channels/chemistry, Ions, Kinetics, Long QT Syndrome/metabolism, Membrane Potentials, Models, Biological, Muscle Cells/metabolism, Mutation, Myocytes, Cardiac/metabolism, Patch-Clamp Techniques, Pericardium/metabolism, Phenotype, Potassium Channels, Voltage-Gated/chemistry, Potassium Channels, Voltage-Gated/physiology, Rabbits, Temperature, Time Factors
Pubmed
Web of science
Open Access
Yes
Create date
01/03/2018 16:40
Last modification date
20/08/2019 17:25
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