title: The S140G KCNQ1 atrial fibrillation mutation affects 'I(KS)' profile during both atrial and ventricular action potentials.
abstract: KCNQ1 is responsible for the pore-forming subunit of channels that mediate the cardiac 'IKs' potassium channel current. The S140G KCNQ1 gain-of-function mutation is responsible for a form of heritable atrial fibrillation. Here the action potential (AP) voltage clamp technique was used to elucidate the effect of S140G KCNQ1 on the profile of recombinant I(Ks) during atrial and ventricular APs applied to KCNQ1+KCNE1 expressing CHO cells, at 37°C. Under conventional voltage clamp the S140G KCNQ1 mutation shifted voltage-dependent activation by ≈-62 mV, with a marked instantaneous current component evident on membrane depolarisation. Under atrial AP clamp, cells expressing wild-type (WT) KCNQ1 exhibited modest outward currents during atrial repolarisation, whilst those expressing S140G KCNQ1 exhibited a marked instantaneous outward current and peak repolarising current >4-fold that for WT KCNQ1. Under ventricular AP clamp, both WT and mutant KCNQ1 conditions showed greater peak repolarising current than when an atrial AP command was used and the S140G mutation resulted in peak repolarising current that was >3-fold that for WT KCNQ1. We conclude that the S140G KCNQ1 mutation would be predicted to augment substantially repolarising current both early and throughout atrial APs and, in principle, also to influence markedly ventricular AP repolarisation.
authors.affiliation: Department of Physiology and Pharmacology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, University Walk, Bristol, UK.
authors.forename: A
authors.initials: A
authors.lastname: El Harchi
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: J C
authors.initials: JC
authors.lastname: Hancox
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D006321:Heart / Q000503:physiopathology*; D006325:Heart Atria / Q000503:physiopathology; D006352:Heart Ventricles / Q000503:physiopathology; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D009154:Mutation; D018408:Patch-Clamp Techniques / Q000379:methods; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*
chemical_list: D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk)