α-Dystrobrevin-1 recruits α-catulin to the α1D-adrenergic receptor/dystrophin-associated protein complex signalosome

alpha(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 alpha(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 alpha(1D)-AR signalosome remains a mystery. To test the hypothesis that previously unidentified molecules are recruited to the alpha(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, alpha-catulin. Coimmunoprecipitation and blot overlay assays indicate that alpha-catulin is directly recruited to the alpha(1D)-AR signalosome by the C-terminal domain of alpha-dystrobrevin-1 and not the closely related splice variant alpha-dystrobrevin-2. Proteomic and biochemical analysis revealed that alpha-catulin supersensitizes alpha(1D)-AR functional responses by recruiting effector molecules to the signalosome. Taken together, our study implicates alpha-catulin as a unique regulator of GPCR signaling and represents a unique expansion of the intricate and continually evolving array of GPCR signaling networks.