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(Circulation Research. 2008;103:1451.)
© 2008 American Heart Association, Inc.

Cellular Biology

Long QT Syndrome–Associated Mutations in KCNQ1 and KCNE1 Subunits Disrupt Normal Endosomal Recycling of I_Ks Channels

Guiscard Seebohm, Nathalie Strutz-Seebohm, Oana N. Ureche, Ulrike Henrion, Ravshan Baltaev, Andreas F. Mack, Ganna Korniychuk, Katja Steinke, Daniel Tapken, Arne Pfeufer, Stefan Kääb, Cecilia Bucci, Bernard Attali, Jean Merot, Jeremy M. Tavare, Uta C. Hoppe, Michael C. Sanguinetti, Florian Lang

From the Department of Physiology I (G.S., N.S.-S., O.N.U., U.H., R.B., A.F.M., G.K., F.L.), University of Tuebingen, Germany; Department of Biochemistry I (G.S., N.S.-S., U.H., K.S., D.T.), Receptor Biochemistry, Ruhr University Bochum, Germany; Institute of Human Genetics (A.P., S.K.), Technical University Munich, Germany; Institute of Human Genetics (A.P., S.K.), National Research Center of Environment and Health, Neuherberg, Germany; Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (C.B.), Università di Lecce, Italy; Department of Physiology and Pharmacology (B.A.), Sackler Medical School, Tel Aviv University, Israel; INSERM U533 (J.M.), Institut du Thorax, Faculté de Médecine, Nantes, France; Department of Biochemistry (J.M.T.), School of Medical Sciences, University of Bristol, England; Department of Internal Medicine III (U.C.H.), Center for Molecular Medicine, University of Cologne, Germany; and Department of Physiology and Nora Eccles Harrison Cardiovascular Research & Training Institute (M.C.S.), University of Utah, Salt Lake City.

Correspondence to Prof Dr Guiscard Seebohm, Biochemistry I, Cation Channel Group, Room NC6/132, Ruhr University Bochum, Universitätsstr. 150, D-44780 Bochum, Germany. E-mail guiscard.seebohm{at}gmx.de

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 (KCNQ1, KvLQT1, Kv7.1) or β (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.

Key Words: kinase • trafficking • PIKfyve • LQT • stress

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