Document Detail


Blood pressure is regulated by an alpha1D-adrenergic receptor/dystrophin signalosome.
MedLine Citation:
PMID:  18468998     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hypertension is a cardiovascular disease associated with increased plasma catecholamines, overactivation of the sympathetic nervous system, and increased vascular tone and total peripheral resistance. A key regulator of sympathetic nervous system function is the alpha(1D)-adrenergic receptor (AR), which belongs to the adrenergic family of G-protein-coupled receptors (GPCRs). Endogenous catecholamines norepinephrine and epinephrine activate alpha(1D)-ARs on vascular smooth muscle to stimulate vasoconstriction, which increases total peripheral resistance and mean arterial pressure. Indeed, alpha(1D)-AR KO mice display a hypotensive phenotype and are resistant to salt-induced hypertension. Unfortunately, little information exists about how this important GPCR functions because of an inability to obtain functional expression in vitro. Here, we identified the dystrophin proteins, syntrophin, dystrobrevin, and utrophin as essential GPCR-interacting proteins for alpha(1D)-ARs. We found that dystrophins complex with alpha(1D)-AR both in vitro and in vivo to ensure proper functional expression. More importantly, we demonstrate that knock-out of multiple syntrophin isoforms results in the complete loss of alpha(1D)-AR function in mouse aortic smooth muscle cells and abrogation of alpha(1D)-AR-mediated increases in blood pressure. Our findings demonstrate that syntrophin and utrophin associate with alpha(1D)-ARs to create a functional signalosome, which is essential for alpha(1D)-AR regulation of vascular tone and blood pressure.
Authors:
John S Lyssand; Mia C DeFino; Xiao-bo Tang; Angie L Hertz; David B Feller; Jennifer L Wacker; Marvin E Adams; Chris Hague
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-05-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-30     Completed Date:  2008-08-19     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18792-800     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic alpha-1 Receptor Agonists
Animals
Aorta / metabolism,  pathology
Cell Line
Dystrophin / genetics,  metabolism*
Dystrophin-Associated Proteins / genetics,  metabolism*
Epinephrine / metabolism
Gene Expression Regulation / genetics
Humans
Hypertension / genetics,  metabolism*,  pathology
Mice
Multiprotein Complexes / genetics,  metabolism*
Muscle Tonus / genetics
Muscle, Smooth, Vascular / metabolism*,  pathology
Norepinephrine / metabolism
Receptors, Adrenergic, alpha-1 / genetics,  metabolism*
Signal Transduction / genetics
Sympathetic Nervous System / metabolism,  pathology
Vascular Resistance / genetics
Grant Support
ID/Acronym/Agency:
5 T32 GM07750/GM/NIGMS NIH HHS; NS33145/NS/NINDS NIH HHS; R01 NS033145-18/NS/NINDS NIH HHS; T32 GM07270/GM/NIGMS NIH HHS; T32 HL07312/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/ADRA1D protein, human; 0/Adra1d protein, mouse; 0/Adrenergic alpha-1 Receptor Agonists; 0/Dystrophin; 0/Dystrophin-Associated Proteins; 0/Multiprotein Complexes; 0/Receptors, Adrenergic, alpha-1; 51-41-2/Norepinephrine; 51-43-4/Epinephrine
Comments/Corrections

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