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(Circulation Research. 2009;104:758.)
© 2009 American Heart Association, Inc.

Cellular Biology

Kv4 Potassium Channels Form a Tripartite Complex With the Anchoring Protein SAP97 and CaMKII in Cardiac Myocytes

Saïd El-Haou, Elise Balse^*, Nathalie Neyroud^*, Gilles Dilanian, Bruno Gavillet, Hugues Abriel, Alain Coulombe, Andreas Jeromin, Stéphane N. Hatem

From the Institut National de la Santé et de la Recherche Médicale and Université Pierre-Marie-Curie-Paris 6 (S.E.-H., E.B., N.N., G.D., A.C., S.N.H.), UMRS 956, Paris, France; Department of Pharmacology and Toxicology, and Service of Cardiology, University of Lausanne (B.G., H.A.), Lausanne, Switzerland; and The Allen Institute for Brain Science (A.J.), Seattle, Wash.

Correspondence to Dr Stéphane N. Hatem, UMRS-956, Faculté de Médecine Pierre-Marie Curie, 91 boulevard de l’Hôpital, 75013 Paris, France. E-mail stephane.hatem{at}upmc.fr

Membrane-associated guanylate kinase (MAGUK) proteins are major determinants of the organization of ion channels in the plasma membrane in various cell types. Here, we investigated the interaction between the MAGUK protein SAP97 and cardiac Kv4.2/3 channels, which account for a large part of the outward potassium current, I_to, in heart. We found that the Kv4.2 and Kv4.3 channels C termini interacted with SAP97 via a SAL amino acid sequence. SAP97 and Kv4.3 channels were colocalized in the sarcolemma of cardiomyocytes. In CHO cells, SAP97 clustered Kv4.3 channels in the plasma membrane and increased the current independently of the presence of KChIP and dipeptidyl peptidase-like protein-6. Suppression of SAP97 by using short hairpin RNA inhibited I_to in cardiac myocytes, whereas its overexpression by using an adenovirus increased I_to. Kv4.3 channels without the SAL sequence were no longer regulated by Ca²⁺/calmodulin kinase (CaMK)II inhibitors. In cardiac myocytes, pull-down and coimmunoprecipitation assays showed that the Kv4 channel C terminus, SAP97, and CaMKII interact together, an interaction suppressed by SAP97 silencing and enhanced by SAP97 overexpression. In HEK293 cells, SAP97 silencing reproduced the effects of CaMKII inhibition on current kinetics and suppressed Kv4/CaMKII interactions. In conclusion, SAP97 is a major partner for surface expression and CaMKII-dependent regulation of cardiac Kv4 channels.

Key Words: potassium channels • cardiac myocytes • MAGUK proteins • calcium/calmodulin-dependent protein kinase • dipeptidyl peptidase–like protein 6

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Sticky Fingers: CaMKII Finds a Home on Another Ion Channel

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