title: The Susceptibilities of Human Ether-à-Go-Go-Related Gene Channel with the G487R Mutation to Arrhythmogenic Factors.
abstract: The human ether-à-go-go-related gene (hERG) channel mediates the rapid delayed rectifier potassium current (IKr) responsible for shaping the repolarization phase of cardiac action potentials. hERG mutation may cause hERG channel malfunction, leading to long QT syndrome and other arrhythmic disorders. Elucidation of the genotype-phenotype relationships of individual hERG mutations is key to the development of treatment for such arrhythmic disorders. We previously identified hERG(G487R), a missense mutant with a glycine-to-arginine substitution at position 487. In the absence of arrhythmogenic factors, hERG(G487R) subunit-containing channels show normal surface expression and gating kinetics. However, it remains unknown whether the mutation exacerbates hERG channel malfunction induced by arrhythmogenic factors. Here we used a voltage-clamp technique to compare the effects of the major arrythmogenic factors on wild-type hERG [hERG(WT)] and hERG(G487R) channel currents (IhERG) in HEK-293T cells. The extent of IhERG blockade by the antiarrhythmic drug dofetilide or E4031 was not different between these channels. On the other hand, the extracellular K(+) concentration ([K(+)]ex)-dependent changes in the rates of recovery from inactivation and deactivation of IhERG were rather less obvious for hERG(G487R) channel than for hERG(WT) channel. These findings suggest that the inheritance of hERG(G487R) does not increase the risk of arrhythmic disorders induced by antiarrhythmic drugs or hypokalemia.
authors.affiliation: Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Hisajima
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hata
authors.forename: Koshi
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Toshiki
authors.initials: T
authors.lastname: Fukushima
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishida
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
authors.forename: Toshihide
authors.initials: T
authors.lastname: Tabata
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000235:genetics*; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005838:Genotype; D057809:HEK293 Cells; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006329:Heart Conduction System / Q000002:abnormalities*; D006801:Humans; D007008:Hypokalemia / Q000150:complications; D015640:Ion Channel Gating / Q000235:genetics; D007700:Kinetics; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics; D009154:Mutation; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000009:adverse effects*; D010641:Phenotype; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D013449:Sulfonamides / Q000009:adverse effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide; D011188:Potassium