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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
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.
*
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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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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