Long QT syndrome-associated mutations in KCNQ1 and KCNE1 subunits disrupt normal endosomal recycling of IKs channels.
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.
Seebohm
Guiscard
G
Department of Physiology I, University of Tuebingen, Germany. guiscard.seebohm@gmx.de
Strutz-Seebohm
Nathalie
N
Ureche
Oana N
ON
Henrion
Ulrike
U
Baltaev
Ravshan
R
Mack
Andreas F
AF
Korniychuk
Ganna
G
Steinke
Katja
K
Tapken
Daniel
D
Pfeufer
Arne
A
Kääb
Stefan
S
Bucci
Cecilia
C
Attali
Bernard
B
Merot
Jean
J
Tavare
Jeremy M
JM
Hoppe
Uta C
UC
Sanguinetti
Michael C
MC
Lang
Florian
F
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
C530745:KCNE1 protein, Xenopus; D051657:KCNQ1 Potassium Channel; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D029867:Xenopus Proteins