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(Circulation Research. 2007;100:686.)
© 2007 American Heart Association, Inc.

Cellular Biology

Regulation of Endocytic Recycling of KCNQ1/KCNE1 Potassium Channels

Guiscard Seebohm^*, Nathalie Strutz-Seebohm^*, Ria Birkin, Ghislaine Dell, Cecilia Bucci, Maria R. Spinosa, Ravshan Baltaev, Andreas F. Mack, Ganna Korniychuk, Amit Choudhury, David Marks, Richard E. Pagano, Bernard Attali, Arne Pfeufer, Robert S. Kass, Michael C. Sanguinetti, Jeremy M. Tavare, Florian Lang^*

From the Department of Physiology I (G.S., N.S.-S., R.B., A.F.M., G.K., F.L.), University of Tuebingen, Germany; Department of Biochemistry (R.B., G.D., J.M.T.), School of Medical Sciences, University of Bristol, England; Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (C.B., M.R.S.) Università di Lecce, Italy; Department of Biochemistry and Molecular Biology (A.C., D.M., R.E.P.), Mayo Clinic and Foundation, Rochester, Minn; Department of Physiology and Pharmacology (B.A.), Sackler Medical School, Tel Aviv University, Israel; Institute of Human Genetics (A.P.), Technical University Munich, Germany; Institute of Human Genetics (A.P.), GSF National Research Center of Environment and Health, Neuherberg, Germany; Department of Pharmacology (R.S.K.), College of Physicians and Surgeons of Columbia University, New York, NY; Department of Physiology and Nora Eccles Harrison Cardiovascular Research & Training Institute (M.C.S.), University of Utah, Salt Lake City.

Correspondence to PD. Dr Guiscard Seebohm, Department of Physiology I, University of Tuebingen, Gmelinstrasse 5, D-72076 Tuebingen, Germany. E-mail guiscard.seebohm{at}gmx.de

Stress-dependent regulation of cardiac action potential duration is mediated by the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. It is accompanied by an increased magnitude of the slow outward potassium ion current, I_Ks. KCNQ1 and KCNE1 subunits coassemble to form the I_Ks channel. Mutations in either subunit cause long QT syndrome, an inherited cardiac arrhythmia associated with an increased risk of sudden cardiac death. Here we demonstrate that exocytosis of KCNQ1 proteins to the plasma membrane requires the small GTPase RAB11, whereas endocytosis is dependent on RAB5. We further demonstrate that RAB-dependent KCNQ1/KCNE1 exocytosis is enhanced by the serum- and glucocorticoid-inducible kinase 1, and requires phosphorylation and activation of phosphoinositide 3-phosphate 5-kinase and the generation of PI(3,5)P₂. Identification of KCNQ1/KCNE1 recycling and its modulation by serum- and glucocorticoid-inducible kinase 1-phosphoinositide 3-phosphate 5-kinase -PI(3,5)P₂ provides a mechanistic insight into stress-induced acceleration of cardiac repolarization.

Key Words: kinase • PIP2 • RAB • trafficking • PIKfyve

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