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First published online 4 December 2007
doi: 10.1242/jcs.020701

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Differential targeting of nNOS and AQP4 to dystrophin-deficient sarcolemma by membrane-directed -dystrobrevin

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

^* Author for correspondence (e-mail: Marva{at}u.washington.edu)

Accepted 11 October 2007

-Dystrobrevin associates with and is a homologue of dystrophin, the protein linked to Duchenne and Becker muscular dystrophies. We used a transgenic approach to restore -dystrobrevin to the sarcolemma in mice that lack dystrophin (mdx mice) to study two interrelated functions: (1) the ability of -dystrobrevin to rescue components of the dystrophin complex in the absence of dystrophin and (2) the ability of sarcolemmal -dystrobrevin to ameliorate the dystrophic phenotype. We generated transgenic mice expressing -dystrobrevin-2a linked to a palmitoylation signal sequence and bred them onto the -dystrobrevin-null and mdx backgrounds. Expression of palmitoylated -dystrobrevin prevented the muscular dystrophy observed in the -dystrobrevin-null mice, demonstrating that the altered form of -dystrobrevin was functional. On the mdx background, the palmitoylated form of -dystrobrevin was expressed on the sarcolemma but did not significantly ameliorate the muscular dystrophy phenotype. Palmitoylated dystrobrevin restored -syntrophin and aquaporin-4 (AQP4) to the mdx sarcolemma but was unable to recruit β-dystroglycan or the sarcoglycans. Despite restoration of sarcolemmal -syntrophin, neuronal nitric oxide synthase (nNOS) was not localized to the sarcolemma, suggesting that nNOS requires both dystrophin and -syntrophin for correct localization. Thus, although nNOS and AQP4 both require interaction with the PDZ domain of -syntrophin for sarcolemmal association, their localization is regulated differentially.

Key words: -Dystrobrevin, Nitric oxide synthase, Aquaporin 4, Syntrophin, Muscular dystrophy, Utrophin

This article has been cited by other articles:

				M. E. Adams, Y. Tesch, J. M. Percival, D. E. Albrecht, J. I. Conhaim, K. Anderson, and S. C. Froehner Differential targeting of nNOS and AQP4 to dystrophin-deficient sarcolemma by membrane-directed {alpha}-dystrobrevin Development, January 15, 2008; 135(2): e1 - e1. [Full Text]