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J. Biol. Chem., Vol. 278, Issue 3, 1915-1923, January 17, 2003

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Syntrophin 2 Regulates SCN5A Gating by a PDZ Domain-mediated Interaction^*

Yijun Ou, Peter Strege, Steven M. Miller, Jonathan Makielski^§, Michael Ackerman^¶, Simon J. Gibbons, and Gianrico Farrugia

From the  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  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 2 was similar to that of SCN5A. Yeast two-hybrid and glutathione S-transferase pull-down experiments show that SCN5A and syntrophin 2 co-express and that the PDZ domain of syntrophin 2 directly interacts with the C terminus of SCN5A. In native cells, disruption of the C terminus-syntrophin 2 PDZ domain interaction using peptides directed against either region result in loss of mechanosensitivity. Co-transfection of syntrophin 2 with SCN5A in HEK293 cells markedly shifts the activation kinetics of SCN5A and reduces the availability of Na⁺ current. We propose that syntrophin 2 is an essential Na⁺ channel-interacting protein required for the full expression of the Na⁺ current and that the SCN5A-syntrophin 2 interaction determines mechanosensitivity and current availability.

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