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

Marvin E. Adams, Yan Tesch, Justin Percival, Douglas E. Albrecht, Jay I. Conhaim, Kendra Anderson, Stanley C. Froehner

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)48-54
Number of pages7
JournalJournal of Cell Science
Volume121
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

Fingerprint

Aquaporin 4
Sarcolemma
Nitric Oxide Synthase Type I
Dystrophin
Membranes
Muscular Dystrophies
dystrobrevin
Sarcoglycans
Dystroglycans
Lipoylation
Inbred mdx Mouse
PDZ Domains
Phenotype
Duchenne Muscular Dystrophy
Protein Sorting Signals
Transgenic Mice

Keywords

  • α-Dystrobrevin
  • Aquaporin 4
  • Muscular dystrophy
  • Nitric oxide synthase
  • Syntrophin
  • Utrophin

ASJC Scopus subject areas

  • Cell Biology

Cite this

Differential targeting of nNOS and AQP4 to dystrophin-deficient sarcolemma by membrane-directed α-dystrobrevin. / Adams, Marvin E.; Tesch, Yan; Percival, Justin; Albrecht, Douglas E.; Conhaim, Jay I.; Anderson, Kendra; Froehner, Stanley C.

In: Journal of Cell Science, Vol. 121, No. 1, 01.01.2008, p. 48-54.

Research output: Contribution to journalArticle

Adams, Marvin E. ; Tesch, Yan ; Percival, Justin ; Albrecht, Douglas E. ; Conhaim, Jay I. ; Anderson, Kendra ; Froehner, Stanley C. / Differential targeting of nNOS and AQP4 to dystrophin-deficient sarcolemma by membrane-directed α-dystrobrevin. In: Journal of Cell Science. 2008 ; Vol. 121, No. 1. pp. 48-54.
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AU - Percival, Justin

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AU - Conhaim, Jay I.

AU - Anderson, Kendra

AU - Froehner, Stanley C.

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

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KW - Syntrophin

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