title: Enhanced inhibitory effect of acidosis on hERG potassium channels that incorporate the hERG1b isoform.
abstract: Extracellular acidosis occurs in the heart during myocardial ischemia and can lead to dangerous arrhythmias. Potassium channels encoded by hERG (human ether-à-go-go-related gene) mediate the cardiac rapid delayed rectifier K+ current (IKr), and impaired hERG function can exacerbate arrhythmia risk. Nearly all electrophysiological investigations of hERG have centred on the hERG1a isoform, although native IKr channels may be comprised of hERG1a and hERG1b, which has a unique shorter N-terminus. This study has characterised for the first time the effects of extracellular acidosis (an extracellular pH decrease from 7.4 to 6.3) on hERG channels incorporating the hERG1b isoform. Acidosis inhibited hERG1b current amplitude to a significantly greater extent than that of hERG1a, with intermediate effects on coexpressed hERG1a/1b. IhERG tail deactivation was accelerated by acidosis for both isoforms. hERG1a/1b activation was positively voltage-shifted by acidosis, and the fully-activated current-voltage relation was reduced in amplitude and right-shifted (by ∼10 mV). Peak IhERG1a/1b during both ventricular and atrial action potentials was both suppressed and positively voltage-shifted by acidosis. Differential expression of hERG isoforms may contribute to regional differences in IKr in the heart. Therefore inhibitory effects of acidosis on IKr could also differ regionally, depending on the relative expression levels of hERG1a and 1b, thereby increasing dispersion of repolarization and arrhythmia risk.
authors.affiliation: School of Physiology and Pharmacology, Bristol Heart Institute, Medical Sciences Building, The University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: C Y
authors.initials: CY
authors.lastname: Du
authors.forename: A
authors.initials: A
authors.lastname: El Harchi
authors.forename: M J
authors.initials: MJ
authors.lastname: McPate
authors.forename: C H
authors.initials: CH
authors.lastname: Orchard
authors.forename: J C
authors.initials: JC
authors.lastname: Hancox
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D020033:Protein Isoforms