title: Syntrophin isoforms play specific functional roles in the α1D-adrenergic receptor/DAPC signalosome.
abstract: α(1D)-Adrenergic receptors, key regulators of cardiovascular system function, are organized as a multi-protein complex in the plasma membrane. Using a Type-I PDZ-binding motif in their distal C-terminal domain, α(1D)-ARs associate with syntrophins and dystrophin-associated protein complex (DAPC) members utrophin, dystrobrevin and α-catulin. Three of the five syntrophin isoforms (α, β(1) and β(2)) interact with α(1D)-ARs and our previous studies suggest multiple isoforms are required for proper α(1D)-AR function in vivo. This study determined the contribution of each specific syntrophin isoform to α(1D)-AR function. Radioligand binding experiments reveal α-syntrophin enhances α(1D)-AR binding site density, while phosphoinositol and ERK1/2 signaling assays indicate β(2)-syntrophin augments full and partial agonist efficacy for coupling to downstream signaling mechanisms. The results of this study provide clear evidence that the cytosolic components within the α(1D)-AR/DAPC signalosome significantly alter the pharmacological properties of α(1)-AR ligands in vitro.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Lyssand
authors.forename: Kyung-Soon
authors.initials: KS
authors.lastname: Lee
authors.forename: Mia
authors.initials: M
authors.lastname: DeFino
authors.forename: Marvin E
authors.initials: ME
authors.lastname: Adams
authors.forename: Chris
authors.initials: C
authors.lastname: Hague
mesh_terms: D000818:Animals; D049028:Dystrophin-Associated Protein Complex / Q000378:metabolism*; D049029:Dystrophin-Associated Proteins / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D049028:Dystrophin-Associated Protein Complex; D049029:Dystrophin-Associated Proteins; D008024:Ligands; D020033:Protein Isoforms; D018340:Receptors, Adrenergic, alpha-1; C091824:syntrophin