Alpha-dystrobrevin-1 recruits alpha-catulin to the alpha1D-adrenergic receptor/dystrophin-associated protein complex signalosome.
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 molecular mechanism by which the DAPC imparts functionality to the α(1D)-AR signalosome remains a mystery. To test the hypothesis that previously unidentified molecules are recruited to the α(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, α-catulin. Coimmunoprecipitation and blot overlay assays indicate that α-catulin is directly recruited to the α(1D)-AR signalosome by the C-terminal domain of α-dystrobrevin-1 and not the closely related splice variant α-dystrobrevin-2. Proteomic and biochemical analysis revealed that α-catulin supersensitizes α(1D)-AR functional responses by recruiting effector molecules to the signalosome. Taken together, our study implicates α-catulin as a unique regulator of GPCR signaling and represents a unique expansion of the intricate and continually evolving array of GPCR signaling networks.
Department of Pharmacology and Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
John S
JS
Lyssand
Jennifer L
JL
Whiting
Kyung-Soon
KS
Lee
Ryan
R
Kastl
Jennifer L
JL
Wacker
Michael R
MR
Bruchas
Mayumi
M
Miyatake
Lorene K
LK
Langeberg
Charles
C
Chavkin
John D
JD
Scott
Richard G
RG
Gardner
Marvin E
ME
Adams
Chris
C
Hague
D049028:Dystrophin-Associated Protein Complex / Q000378:metabolism*; D049029:Dystrophin-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051178:alpha Catenin / Q000235:genetics / Q000378:metabolism*
D049028:Dystrophin-Associated Protein Complex; D049029:Dystrophin-Associated Proteins; D034741:RNA, Small Interfering; D018340:Receptors, Adrenergic, alpha-1; D051178:alpha Catenin; C098885:dystrobrevin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11