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J. Biol. Chem., Vol. 280, Issue 29, 27289-27295, July 22, 2005

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Selective Inhibition of _1A-Adrenergic Receptor Signaling by RGS2 Association with the Receptor Third Intracellular Loop^*

Chris Hague, Leah S. Bernstein¶, Suneela Ramineni, Zhongjian Chen, Kenneth P. Minneman, and John R. Hepler

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

Regulators of G-protein signaling (RGS) proteins act directly on G subunits to increase the rate of GTP hydrolysis and to terminate signaling. However, the mechanisms involved in determining their specificities of action in cells remain unclear. Recent evidence has raised the possibility that RGS proteins may interact directly with G-protein-coupled receptors to modulate their activity. By using biochemical, fluorescent imaging, and functional approaches, we found that RGS2 binds directly and selectively to the third intracellular loop of the _1A-adrenergic receptor (AR) in vitro, and is recruited by the unstimulated _1A-AR to the plasma membrane in cells to inhibit receptor and G_q/11 signaling. This interaction was specific, because RGS2 did not interact with the highly homologous _1B- or _1D-ARs, and the closely related RGS16 did not interact with any ₁-ARs. The N terminus of RGS2 was required for association with _1A-ARs and inhibition of signaling, and amino acids Lys²¹⁹, Ser²²⁰, and Arg²³⁸ within the _1A-AR i3 loop were found to be essential for this interaction. These findings demonstrate that certain RGS proteins can directly interact with preferred G-protein-coupled receptors to modulate their signaling with a high degree of specificity.

Received for publication, March 2, 2005 , and in revised form, May 4, 2005.

^* This work was supported in part by National Institutes of Health Grants R01-NS37112 and R01-GM61847 (to J. R. 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.

Both authors contributed equally to this work.

^¶ Supported by American Heart Foundation SE Affiliate Postdoctoral Fellowship 0325259B.

Supported by American Heart Foundation SE Affiliate Postdoctoral Fellowship 0425341B. To whom correspondence should be addressed: Dept. of Pharmacology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322. Tel.: 404-727-0363; Fax: 404-727-0365; E-mail: chague{at}emory.edu.

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