title: Channel sialic acids limit hERG channel activity during the ventricular action potential.
abstract: Activity of human ether-a-go-go-related gene (hERG) 1 voltage-gated K(+) channels is responsible for portions of phase 2 and phase 3 repolarization of the human ventricular action potential. Here, we questioned whether and how physiologically and pathophysiologically relevant changes in surface N-glycosylation modified hERG channel function. Voltage-dependent hERG channel gating and activity were evaluated as expressed in a set of Chinese hamster ovary (CHO) cell lines under conditions of full glycosylation, no sialylation, no complex N-glycans, and following enzymatic deglycosylation of surface N-glycans. For each condition of reduced glycosylation, hERG channel steady-state activation and inactivation relationships were shifted linearly by significant depolarizing ∼9 and ∼18 mV, respectively. The hERG window current increased significantly by 50-150%, and the peak shifted by a depolarizing ∼10 mV. There was no significant change in maximum hERG current density. Deglycosylated channels were significantly more active (20-80%) than glycosylated controls during phases 2 and 3 of action potential clamp protocols. Simulations of hERG current and ventricular action potentials corroborated experimental data and predicted reduced sialylation leads to a 50-70-ms decrease in action potential duration. The data describe a novel mechanism by which hERG channel gating is modulated through physiologically and pathophysiologically relevant changes in N-glycosylation; reduced channel sialylation increases hERG channel activity during the action potential, thereby increasing the rate of action potential repolarization.
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Norring
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Ednie
authors.forename: Tara A
authors.initials: TA
authors.lastname: Schwetz
authors.forename: Dongping
authors.initials: D
authors.lastname: Du
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Eric S
authors.initials: ES
authors.lastname: Bennett
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D008955:Models, Cardiovascular; D018408:Patch-Clamp Techniques; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011994:Recombinant Proteins; D012794:Sialic Acids