Long QT syndrome - associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels

G Seebohm, N Strutz-Seebohm, O.N Ureche, U Henrion, R Baltaev, A.F Mack, G Korniychuk, K Steinke, D Tapken, A Pfeufer, S Kääb, C Bucci, B Attali, J Merot, J.M Tavaré, U.C Hoppe, M.C Sanguinetti, F Lang

Research output: Contribution to journalArticle (Academic Journal)peer-review

64 Citations (Scopus)

Abstract

AB mdash;: 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 IKs, a slow delayed rectifier potassium current that mediates cardiac action potential repolarization. Mutations in IKs 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 IKs 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 IKs channels by SGK1 depends on residues H73, N75, D76, and P77 in KCNE1. Identification of the IKs recycling pathway and its modulation by stress-stimulated SGK1 provides novel mechanistic insight into potentially fatal cardiac arrhythmias triggered by physical or psychological stress. (C) 2008 American Heart Association, Inc.
Translated title of the contributionLong QT syndrome - associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels
Original languageEnglish
Pages (from-to)1451 - 1457
Number of pages7
JournalCirculation Research
Volume103
Issue number12
DOIs
Publication statusPublished - Dec 2008

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