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Originally published In Press as doi:10.1074/jbc.M209938200 on November 11, 2002

J. Biol. Chem., Vol. 278, Issue 3, 1915-1923, January 17, 2003
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Syntrophin gamma 2 Regulates SCN5A Gating by a PDZ Domain-mediated Interaction*

Yijun OuDagger , Peter StregeDagger , Steven M. MillerDagger , Jonathan Makielski§, Michael Ackerman, Simon J. GibbonsDagger , and Gianrico FarrugiaDagger ||

From the Dagger  Enteric NeuroScience Program, Department of Physiology and Biophysics and Division of Gastroenterology and Hepatology and the  Departments of Internal Medicine (Cardiovascular Diseases), Pediatrics (Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905 and the § Department of Medicine, University of Wisconsin, Madison, Wisconsin 53706

SCN5A encodes the alpha  subunit of the cardiac muscle and intestinal smooth muscle mechanosensitive Na+ channel. Mechanosensitivity in the intestine requires an intact cytoskeleton. We report, using laser capture microdissection, single cell PCR, and immunohistochemistry, that syntrophins, scaffolding proteins, were expressed in human intestinal smooth muscle cells. The distribution of syntrophin gamma 2 was similar to that of SCN5A. Yeast two-hybrid and glutathione S-transferase pull-down experiments show that SCN5A and syntrophin gamma 2 co-express and that the PDZ domain of syntrophin gamma 2 directly interacts with the C terminus of SCN5A. In native cells, disruption of the C terminus-syntrophin gamma 2 PDZ domain interaction using peptides directed against either region result in loss of mechanosensitivity. Co-transfection of syntrophin gamma 2 with SCN5A in HEK293 cells markedly shifts the activation kinetics of SCN5A and reduces the availability of Na+ current. We propose that syntrophin gamma 2 is an essential Na+ channel-interacting protein required for the full expression of the Na+ current and that the SCN5A-syntrophin gamma 2 interaction determines mechanosensitivity and current availability.

* This work was supported by National Institutes of Health Grants DK52766, DK57061, DK17238, EY03282, and EY06005.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Enteric NeuroScience Program, Guggenheim 8, Mayo Clinic and Mayo Foundation, 200 First St., SW, Rochester, MN 55905. Tel.: 507-284-4695; Fax: 507-284-0266; E-mail: farrugia.gianrico@mayo.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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