Dataset Information

Alpha-dystrobrevin-1 recruits alpha-catulin to the alpha1D-adrenergic receptor/dystrophin-associated protein complex signalosome.

ABSTRACT: ?(1D)-Adrenergic receptors (ARs) are key regulators of cardiovascular system function that increase blood pressure and promote vascular remodeling. Unfortunately, little information exists about the signaling pathways used by this important G protein-coupled receptor (GPCR). We recently discovered that ?(1D)-ARs form a "signalosome" with multiple members of the dystrophin-associated protein complex (DAPC) to become functionally expressed at the plasma membrane and bind ligands. However, the molecular mechanism by which the DAPC imparts functionality to the ?(1D)-AR signalosome remains a mystery. To test the hypothesis that previously unidentified molecules are recruited to the ?(1D)-AR signalosome, we performed an extensive proteomic analysis on each member of the DAPC. Bioinformatic analysis of our proteomic data sets detected a common interacting protein of relatively unknown function, ?-catulin. Coimmunoprecipitation and blot overlay assays indicate that ?-catulin is directly recruited to the ?(1D)-AR signalosome by the C-terminal domain of ?-dystrobrevin-1 and not the closely related splice variant ?-dystrobrevin-2. Proteomic and biochemical analysis revealed that ?-catulin supersensitizes ?(1D)-AR functional responses by recruiting effector molecules to the signalosome. Taken together, our study implicates ?-catulin as a unique regulator of GPCR signaling and represents a unique expansion of the intricate and continually evolving array of GPCR signaling networks.

SUBMITTER: Lyssand JS

PROVIDER: S-EPMC3003112 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Alpha-dystrobrevin-1 recruits alpha-catulin to the alpha1D-adrenergic receptor/dystrophin-associated protein complex signalosome.

Lyssand John S JS Whiting Jennifer L JL Lee Kyung-Soon KS Kastl Ryan R Wacker Jennifer L JL Bruchas Michael R MR Miyatake Mayumi M Langeberg Lorene K LK Chavkin Charles C Scott John D JD Gardner Richard G RG Adams Marvin E ME Hague Chris C

Proceedings of the National Academy of Sciences of the United States of America 20101129 50

α(1D)-Adrenergic receptors (ARs) are key regulators of cardiovascular system function that increase blood pressure and promote vascular remodeling. Unfortunately, little information exists about the signaling pathways used by this important G protein-coupled receptor (GPCR). We recently discovered that α(1D)-ARs form a "signalosome" with multiple members of the dystrophin-associated protein complex (DAPC) to become functionally expressed at the plasma membrane and bind ligands. However, the mole ...[more]

PMID: 21115837

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Project description:BackgroundDystrophins and dystrobrevins are distantly related proteins with important but poorly understood roles in the function of metazoan muscular and neuronal tissues. Defects in them and their associated proteins cause a range of neuromuscular disorders. Members of this superfamily have been discovered in a relatively serendipitous way; we set out to compile a comprehensive description of dystrophin- and dystrobrevin-related sequences from available metazoan genome sequences, validated in representative organisms by RT-PCR, or acquired de novo from key species.ResultsFeatures of the superfamily revealed by our survey include: a) Dystrotelin, an entirely novel branch of the superfamily, present in most vertebrates examined. Dystrotelin is expressed in the central nervous system, and is a possible orthologue of Drosophila DAH. We describe the preliminary characterisation of its function, evolution and expression. b) A novel vertebrate member of the dystrobrevin family, gamma-dystrobrevin, an ancient branch now extant only in fish, but probably present in our own ancestors. Like dystrophin, zebrafish gamma-dystrobrevin mRNA is localised to myosepta. c) The extent of conservation of alternative splicing and alternative promoter use in the dystrophin and dystrobrevin genes; alternative splicing of dystrophin exons 73 and 78 and alpha-dystrobrevin exon 13 are conserved across vertebrates, as are the use of the Dp116, Dp71 and G-utrophin promoters; the Dp260 and Dp140 promoters are tetrapod innovations. d) The evolution of the unique N-terminus of DRP2 and its relationship to Dp116 and G-utrophin. e) A C-terminally truncated common ancestor of dystrophin and utrophin in cyclostomes. f) A severely restricted repertoire of dystrophin complex components in ascidians.ConclusionWe have refined our understanding of the evolutionary history and isoform diversity of the five previously reported vertebrate superfamily members and describe two novel members, dystrotelin and gamma-dystrobrevin. Dystrotelins, dystrophins and dystrobrevins are roughly equally related to each other. Vertebrates therefore have a repertoire of seven superfamily members (three dystrophins, three dystrobevins, and one dystrotelin), with one lost in tetrapods. Most invertebrates studied have one member from each branch. Although the basic shared function which is implied by the common architecture of these distantly related proteins remains unclear, it clearly permeates metazoan biology.

Dataset Information

Alpha-dystrobrevin-1 recruits alpha-catulin to the alpha1D-adrenergic receptor/dystrophin-associated protein complex signalosome.

Publications

Alpha-dystrobrevin-1 recruits alpha-catulin to the alpha1D-adrenergic receptor/dystrophin-associated protein complex signalosome.

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