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J. Biol. Chem., Vol. 283, Issue 27, 18792-18800, July 4, 2008

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Blood Pressure Is Regulated by an _1D-Adrenergic Receptor/Dystrophin Signalosome^*

John S. Lyssand, Mia C. DeFino, Xiao-bo Tang, Angie L. Hertz, David B. Feller, Jennifer L. Wacker, Marvin E. Adams, and Chris Hague¹

From the Department of Pharmacology and Physiology and Biophysics, University of Washington, Seattle, Washington 98195

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 _1D-adrenergic receptor (AR), which belongs to the adrenergic family of G-protein-coupled receptors (GPCRs). Endogenous catecholamines norepinephrine and epinephrine activate _1D-ARs on vascular smooth muscle to stimulate vasoconstriction, which increases total peripheral resistance and mean arterial pressure. Indeed, _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 _1D-ARs. We found that dystrophins complex with _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 _1D-AR function in mouse aortic smooth muscle cells and abrogation of _1D-AR-mediated increases in blood pressure. Our findings demonstrate that syntrophin and utrophin associate with _1D-ARs to create a functional signalosome, which is essential for _1D-AR regulation of vascular tone and blood pressure.

Received for publication, March 7, 2008 , and in revised form, May 5, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Public Health Service Grant NRSA T32 GM07270 from NIGMS (to J. S. L.), by National Institutes of Health Grants 5 T32 GM07750 (to M. C. D. and A. L. H.) and NS33145 (to M. E. A.), and NHLBI, National Institutes of Health Grant T32 HL07312 (to J. L. W.). This work was also supported by American Heart Association Grant 0665487Z (to C. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 1959 NE Pacific St., Box 357280, Seattle, WA 98195. Fax: 206-685-3822; E-mail: chague{at}u.washington.edu.

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