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(Circulation Research. 2009;105:523.)
© 2009 American Heart Association, Inc.

Cellular Biology

Loss of Plakophilin-2 Expression Leads to Decreased Sodium Current and Slower Conduction Velocity in Cultured Cardiac Myocytes

Priscila Y. Sato, Hassan Musa, Wanda Coombs, Guadalupe Guerrero-Serna, Gustavo A. Patiño, Steven M. Taffet, Lori L. Isom, Mario Delmar

From the Center for Arrhythmia Research (P.Y.S., H.M., G.G.-S., M.D.), Department of Medicine; and Department of Pharmacology and Neuroscience Program (G.A.P., L.L.I.), University of Michigan, Ann Arbor; and Departments of Pharmacology (P.Y.S.) and Microbiology and Immunology (W.C., S.M.T.), State University of New York Upstate Medical University, Syracuse.

Correspondence to Mario Delmar, MD, PhD, Center for Arrhythmia Research, University of Michigan, 5025 Venture Dr, Ann Arbor, MI 48108. E-mail mdelmar{at}umich.edu

Rationale: Plakophilin-2 (PKP2) is an essential component of the cardiac desmosome. Recent data show that it interacts with other molecules of the intercalated disc. Separate studies show preferential localization of the voltage-gated sodium channel (Na_V1.5) to this region.

Objective: To establish the association of PKP2 with sodium channels and its role on action potential propagation.

Methods and Results: Biochemical, patch clamp, and optical mapping experiments demonstrate that PKP2 associates with Na_V1.5, and that knockdown of PKP2 expression alters the properties of the sodium current, and the velocity of action potential propagation in cultured cardiomyocytes.

Conclusions: These results emphasize the importance of intermolecular interactions between proteins relevant to mechanical junctions, and those involved in electric synchrony. Possible relevance to the pathogenesis of arrhythmogenic right ventricular cardiomyopathy is discussed.

Key Words: plakophilin-2 • intercalated disc • arrhythmogenic right ventricular cardiomyopathy • cardiac desmosomes