title: Involvement of caveolin in low K+-induced endocytic degradation of cell-surface human ether-a-go-go-related gene (hERG) channels.
abstract: Reduction in the rapidly activating delayed rectifier K(+) channel current (I(Kr)) due to either mutations in the human ether-a-go-go-related gene (hERG) or drug block causes inherited or drug-induced long QT syndrome. A reduction in extracellular K(+) concentration ([K(+)](o)) exacerbates long QT syndrome. Recently, we demonstrated that lowering [K(+)](o) promotes degradation of I(Kr) in rabbit ventricular myocytes and of the hERG channel stably expressed in HEK 293 cells. In this study, we investigated the degradation pathways of hERG channels under low K(+) conditions. We demonstrate that under low K(+) conditions, mature hERG channels and caveolin-1 (Cav1) displayed a parallel time-dependent reduction. Mature hERG channels coprecipitated with Cav1 in co-immunoprecipitation analysis, and internalized hERG channels colocalized with Cav1 in immunocytochemistry analysis. Overexpression of Cav1 accelerated internalization of mature hERG channels in 0 mM K(+)(o), whereas knockdown of Cav1 impeded this process. In addition, knockdown of dynamin 2 using siRNA transfection significantly impeded hERG internalization and degradation under low K(+)(o) conditions. In cultured neonatal rat ventricular myocytes, knockdown of caveolin-3 significantly impeded low K(+)(o)-induced reduction of I(Kr). Our data indicate that a caveolin-dependent endocytic route is involved in low K(+)(o)-induced degradation of mature hERG channels.
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Hamid
authors.initials: H
authors.lastname: Massaeli
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Xian
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Heidi
authors.initials: H
authors.lastname: Shallow
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Wentao
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Hanson
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: shetuan.zhang@queensu.ca.
authors.forename: Shetuan
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D034285:Dynamin II / Q000235:genetics / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D004705:Endocytosis; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C495540:CAV1 protein, human; C495537:Cav1 protein, rat; D051242:Caveolin 1; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D034741:RNA, Small Interfering; D034285:Dynamin II; D011188:Potassium