title: Concerted all-or-none subunit interactions mediate slow deactivation of human ether-à-go-go-related gene K+ channels.
abstract: During the repolarization phase of a cardiac action potential, hERG1 K(+) channels rapidly recover from an inactivated state then slowly deactivate to a closed state. The resulting resurgence of outward current terminates the plateau phase and is thus a key regulator of action potential duration of cardiomyocytes. The intracellular N-terminal domain of the hERG1 subunit is required for slow deactivation of the channel as its removal accelerates deactivation 10-fold. Here we investigate the stoichiometry of hERG1 channel deactivation by characterizing the kinetic properties of concatenated tetramers containing a variable number of wild-type and mutant subunits. Three mutations known to accelerate deactivation were investigated, including R56Q and R4A/R5A in the N terminus and F656I in the S6 transmembrane segment. In all cases, a single mutant subunit induced the same rapid deactivation of a concatenated channel as that observed for homotetrameric mutant channels. We conclude that slow deactivation gating of hERG1 channels involves a concerted, fully cooperative interaction between all four wild-type channel subunits.
authors.affiliation: From the Nora Eccles Harrison Cardiovascular Research and Training Institute and.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Thomson
authors.affiliation: From the Nora Eccles Harrison Cardiovascular Research and Training Institute and.
authors.forename: Angela
authors.initials: A
authors.lastname: Hansen
authors.affiliation: From the Nora Eccles Harrison Cardiovascular Research and Training Institute and Department of Internal Medicine and Division of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah 84112 sanguinetti@cvrti.utah.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
mesh_terms: D000818:Animals; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007700:Kinetics; D009154:Mutation; D014982:Xenopus laevis
chemical_list: D051638:Ether-A-Go-Go Potassium Channels
keywords: Biophysics; Cooperativity; Gating; Potassium Channel; hERG