title: hERG1a/1b heteromeric currents exhibit amplified attenuation of inactivation in variant 1 short QT syndrome.
abstract: Potassium channels encoded by hERG (human ether-à-go-go-related gene) underlie the cardiac rapid delayed rectifier K+ current (IKr) and hERG mutations underpin clinically important repolarization disorders. Virtually all electrophysiological investigations of hERG mutations have studied exclusively the hERG1a isoform; however, recent evidence indicates that native IKr channels may be comprised of hERG1a together with the hERG1b variant, which has a shorter N-terminus. Here, for the first time, electrophysiological effects were studied of a gain-of-function hERG mutation (N588K; responsible for the 'SQT1' variant of the short QT syndrome) on current (I(hERG1a/1b)) carried by co-expressed hERG1a/1b channels. There were no significant effects of N588K on I(hERG1a/1b) activation or deactivation, but N588K I(hERG1a/1b) showed little inactivation up to highly positive voltages (< or = +80 mV), a more marked effect than seen for hERG1a expressed alone. I(hERG1a/1b) under action potential voltage-clamp, and the effects on this of the N588K mutation, also showed differences from those previously reported for hERG1a. The amplified attenuation of I(hERG) inactivation for the N588K mutation reported here indicates that the study of co-expressed hERG1a/1b channels should be considered when investigating clinically relevant hERG channel mutations, even if these reside outside of the N-terminus region.
authors.affiliation: Department of Physiology and Pharmacology, Bristol Heart Institute, School of Medical Sciences, The University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: McPate
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: J M
authors.initials: JM
authors.lastname: Cordeiro
authors.forename: C E
authors.initials: CE
authors.lastname: Dempsey
authors.forename: H J
authors.initials: HJ
authors.lastname: Witchel
authors.forename: J C
authors.initials: JC
authors.lastname: Hancox
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology*; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009154:Mutation
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human