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Published online 24 September 2001. doi:10.1083/jcb.200106158
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© The Rockefeller University Press, 0021-9525/2001/10/113 $5.00
The Journal of Cell Biology, Volume 155, Number 1, October 1, 2001 113-122

Article

In vivo requirement of the {alpha}-syntrophin PDZ domain for the sarcolemmal localization of nNOS and aquaporin-4



Marvin E. Adams, Heather A. Mueller and Stanley C. Froehner

Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195

Address correspondence to Stanley Froehner, Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195-7290. Tel.: (206) 543-0950. Fax: (206) 685-0619. E-mail: froehner{at}u.washington.edu

{alpha}-Syntrophin is a scaffolding adapter protein expressed primarily on the sarcolemma of skeletal muscle. The COOH-terminal half of {alpha}-syntrophin binds to dystrophin and related proteins, leaving the PSD-95, discs-large, ZO-1 (PDZ) domain free to recruit other proteins to the dystrophin complex. We investigated the function of the PDZ domain of {alpha}-syntrophin in vivo by generating transgenic mouse lines expressing full-length {alpha}-syntrophin or a mutated {alpha}-syntrophin lacking the PDZ domain ({Delta}PDZ). The {Delta}PDZ {alpha}-syntrophin displaced endogenous {alpha}- and ß1-syntrophin from the sarcolemma and resulted in sarcolemma containing little or no syntrophin PDZ domain. As a consequence, neuronal nitric oxide synthase (nNOS) and aquaporin-4 were absent from the sarcolemma. However, the sarcolemmal expression and distribution of muscle sodium channels, which bind the {alpha}-syntrophin PDZ domain in vitro, were not altered. Both transgenic mouse lines were bred with an {alpha}-syntrophin–null mouse which lacks sarcolemmal nNOS and aquaporin-4. The full-length {alpha}-syntrophin, not the {Delta}PDZ form, reestablished nNOS and aquaporin-4 at the sarcolemma of these mice. Genetic crosses with the mdx mouse showed that neither transgenic syntrophin could associate with the sarcolemma in the absence of dystrophin. Together, these data show that the sarcolemmal localization of nNOS and aquaporin-4 in vivo depends on the presence of a dystrophin-bound {alpha}-syntrophin PDZ domain.

Key Words: syntrophin; aquaporin; dystrophin complex; neuronal nitric oxide synthase; PDZ domain


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