title: Long QT syndrome-associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels.
abstract: Physical and emotional stress is accompanied by release of stress hormones such as the glucocorticoid cortisol. This hormone upregulates the serum- and glucocorticoid-inducible kinase (SGK)1, which in turn stimulates I(Ks), a slow delayed rectifier potassium current that mediates cardiac action potential repolarization. Mutations in I(Ks) channel alpha (KCNQ1, KvLQT1, Kv7.1) or beta (KCNE1, IsK, minK) subunits cause long QT syndrome (LQTS), an inherited cardiac arrhythmia associated with increased risk of sudden death. Together with the GTPases RAB5 and RAB11, SGK1 facilitates membrane recycling of KCNQ1 channels. Here, we show altered SGK1-dependent regulation of LQTS-associated mutant I(Ks) channels. Whereas some mutant KCNQ1 channels had reduced basal activity but were still activated by SGK1, currents mediated by KCNQ1(Y111C) or KCNQ1(L114P) were paradoxically reduced by SGK1. Heteromeric channels coassembled of wild-type KCNQ1 and the LQTS-associated KCNE1(D76N) mutant were similarly downregulated by SGK1 because of a disrupted RAB11-dependent recycling. Mutagenesis experiments indicate that stimulation of I(Ks) channels by SGK1 depends on residues H73, N75, D76, and P77 in KCNE1. Identification of the I(Ks) recycling pathway and its modulation by stress-stimulated SGK1 provides novel mechanistic insight into potentially fatal cardiac arrhythmias triggered by physical or psychological stress.
authors.affiliation: Department of Physiology I, University of Tuebingen, Germany. guiscard.seebohm@gmx.de
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strutz-Seebohm
authors.forename: Oana N
authors.initials: ON
authors.lastname: Ureche
authors.forename: Ulrike
authors.initials: U
authors.lastname: Henrion
authors.forename: Ravshan
authors.initials: R
authors.lastname: Baltaev
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Mack
authors.forename: Ganna
authors.initials: G
authors.lastname: Korniychuk
authors.forename: Katja
authors.initials: K
authors.lastname: Steinke
authors.forename: Daniel
authors.initials: D
authors.lastname: Tapken
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bucci
authors.forename: Bernard
authors.initials: B
authors.lastname: Attali
authors.forename: Jean
authors.initials: J
authors.lastname: Merot
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Tavare
authors.forename: Uta C
authors.initials: UC
authors.lastname: Hoppe
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D011992:Endosomes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000502:physiology; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D029867:Xenopus Proteins / Q000235:genetics* / Q000502:physiology; D014982:Xenopus laevis
chemical_list: C530745:KCNE1 protein, Xenopus; D051657:KCNQ1 Potassium Channel; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D029867:Xenopus Proteins