title: Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines.
abstract: Although the modulation of ion channel gating by hormones and drugs has been extensively studied, much less is known about how cell surface ion channel expression levels are regulated. Here, we demonstrate that the cell surface density of both the heterologously expressed K+ channel encoded by the human ether-a-go-go-related gene (HERG) and its native counterpart, the rapidly activating delayed rectifier K+ channel (IKr), in rabbit hearts in vivo is precisely controlled by extracellular K+ concentration ([K+]o) within a physiologically relevant range. Reduction of [K+]o led to accelerated internalization and degradation of HERG channels within hours. Confocal analysis revealed colocalization between HERG and ubiquitin during the process of HERG internalization, and overexpression of ubiquitin facilitated HERG degradation under low [K+]o. The HERG channels colocalized with a marker of multivesicular bodies during internalization, and the internalized HERG channels were targeted to lysosomes. Our results provide the first evidence to our knowledge that the cell surface density of a voltage-gated K+ channel, HERG, is regulated by a biological factor, extracellular K+. Because hypokalemia is known to exacerbate long QT syndrome (LQTS) and Torsades de pointes tachyarrhythmias, our findings provide a potential mechanistic link between hypokalemia and LQTS.
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Hamid
authors.initials: H
authors.lastname: Massaeli
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xu
authors.forename: Zongchao
authors.initials: Z
authors.lastname: Jia
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Wigle
authors.forename: Nasrin
authors.initials: N
authors.lastname: Mesaeli
authors.forename: Shetuan
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D006801:Humans; D007008:Hypokalemia / Q000150:complications / Q000378:metabolism; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D017419:Potassium, Dietary / Q000008:administration & dosage; D011817:Rabbits; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D017419:Potassium, Dietary; D025801:Ubiquitin; D011188:Potassium