title: Interaction between the cardiac rapidly (IKr) and slowly (IKs) activating delayed rectifier potassium channels revealed by low K+-induced hERG endocytic degradation.
abstract: Cardiac repolarization is controlled by the rapidly (I(Kr)) and slowly (I(Ks)) activating delayed rectifier potassium channels. The human ether-a-go-go-related gene (hERG) encodes I(Kr), whereas KCNQ1 and KCNE1 together encode I(Ks). Decreases in I(Kr) or I(Ks) cause long QT syndrome (LQTS), a cardiac disorder with a high risk of sudden death. A reduction in extracellular K(+) concentration ([K(+)](o)) induces LQTS and selectively causes endocytic degradation of mature hERG channels from the plasma membrane. In the present study, we investigated whether I(Ks) compensates for the reduced I(Kr) under low K(+) conditions. Our data show that when hERG and KCNQ1 were expressed separately in human embryonic kidney (HEK) cells, exposure to 0 mM K(+) for 6 h completely eliminated the mature hERG channel expression but had no effect on KCNQ1. When hERG and KCNQ1 were co-expressed, KCNQ1 significantly delayed 0 mM K(+)-induced hERG reduction. Also, hERG degradation led to a significant reduction in KCNQ1 in 0 mM K(+) conditions. An interaction between hERG and KCNQ1 was identified in hERG+KCNQ1-expressing HEK cells. Furthermore, KCNQ1 preferentially co-immunoprecipitated with mature hERG channels that are localized in the plasma membrane. Biophysical and pharmacological analyses indicate that although hERG and KCNQ1 closely interact with each other, they form distinct hERG and KCNQ1 channels. These data extend our understanding of delayed rectifier potassium channel trafficking and regulation, as well as the pathology of LQTS.
authors.affiliation: Department of Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Tingzhong
authors.initials: T
authors.lastname: Wang
authors.forename: Tonghua
authors.initials: T
authors.lastname: Yang
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xu
authors.forename: Wentao
authors.initials: W
authors.lastname: Li
authors.forename: Michael D
authors.initials: MD
authors.lastname: Fridman
authors.forename: John T
authors.initials: JT
authors.lastname: Fisher
authors.forename: Shetuan
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001703:Biophysics / Q000379:methods; D002462:Cell Membrane / Q000378:metabolism; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism*; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology / Q000379:methods; D004705:Endocytosis; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology*; D006321:Heart / Q000502:physiology; D006801:Humans; D007008:Hypokalemia / Q000378:metabolism; D051657:KCNQ1 Potassium Channel / Q000378:metabolism; D007668:Kidney / Q000196:embryology; D009206:Myocardium / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011817:Rabbits
chemical_list: D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated; D011188:Potassium