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J. Biol. Chem., Vol. 281, Issue 18, 12414-12420, May 5, 2006

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Syntrophins Regulate _1D-Adrenergic Receptors through a PDZ Domain-mediated Interaction^*

From the Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322

To find novel cytoplasmic binding partners of the _1D-adrenergic receptor (AR), a yeast two-hybrid screen using the _1D-AR C terminus as bait was performed on a human brain cDNA library. -Syntrophin, a protein containing one PDZ domain and two pleckstrin homology domains, was isolated in this screen as an _1D-AR-interacting protein. -Syntrophin specifically recognized the C terminus of _1D- but not _1A- or _1B-ARs. In blot overlay assays, the PDZ domains of syntrophin isoforms , 1, and 2 but not 1 or 2 showed strong selective interactions with the _1D-AR C-tail fusion protein. In transfected human embryonic kidney 293 cells, full-length _1D- but not _1A- or _1B-ARs co-immunoprecipitated with syntrophins, and the importance of the receptor C terminus for the _1D-AR/syntrophin interaction was confirmed using chimeric receptors. Mutation of the PDZ-interacting motif at the _1D-AR C terminus markedly decreased inositol phosphate formation stimulated by norepinephrine but not carbachol in transfected HEK293 cells. This mutation also dramatically decreased _1D-AR binding and protein expression. In addition, stable overexpression of -syntrophin significantly increased _1D-AR protein expression and binding but did not affect those with a mutated PDZ-interacting motif, suggesting that syntrophin plays an important role in maintaining receptor stability by directly interacting with the receptor PDZ-interacting motif. This direct interaction may provide new information about the regulation of _1D-AR signaling and the role of syntrophins in modulating G protein-coupled receptor function.

Received for publication, August 5, 2005 , and in revised form, January 25, 2006.

^* This work was supported by National Institutes of Health grants (to K. P. M. and R. A. H.), a Keck foundation award (to R. A. H.), an American Heart Association postdoctoral fellowship (to C. H.), and an American Heart Association grant-in-aid (to K. P. M.). 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. Tel.: 404-727-5985; Fax: 404-727-0365; E-mail kminneman{at}pharm.emory.edu.

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