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J. Biol. Chem., Vol. 279, Issue 15, 15541-15549, April 9, 2004

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Cell Surface Expression of _1D-Adrenergic Receptors Is Controlled by Heterodimerization with _1B-Adrenergic Receptors^*

Chris Hague, Michelle A. Uberti, Zhongjian Chen, Randy A. Hall, and Kenneth P. Minneman¶

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

₁-Adrenergic receptors (ARs) belong to the large Class I G protein-coupled receptor superfamily and comprise three subtypes (_1A, _1B, and _1D). Previous work with heterologously expressed C-terminal green fluorescent protein (GFP)-tagged ₁-ARs showed that _1A- and _1B-ARs localize to the plasma membrane, whereas _1D-ARs accumulate intracellularly. We recently showed that _1D- and _1B-ARs form heterodimers, whereas _1D- and _1A-ARs do not. Here, we examined the role of heterodimerization in regulating _1D-AR localization using both confocal imaging of GFP- or CFP-tagged ₁-ARs and a luminometer-based surface expression assay in HEK293 cells. Co-expression with _1B-ARs caused _1D-ARs to quantitatively translocate to the cell surface, but co-expression with _1A-ARs did not. Truncation of the _1B-AR extracellular N terminus or intracellular C terminus had no effect on surface expression of _1D-ARs, suggesting primary involvement of the hydrophobic core. Co-transfection with an uncoupled mutant _1B-AR (12_1B) increased both _1D-AR surface expression and coupling to norepinephrine-stimulated Ca²⁺ mobilization. Finally, GFP-tagged _1D-ARs were not detected on the cell surface when expressed in rat aortic smooth muscle cells that express no endogenous ARs, but were almost exclusively localized on the surface when expressed in DDT₁MF-2 cells, which express endogenous _1B-ARs. These studies demonstrate that _1B/_1D-AR heterodimerization controls surface expression and functional coupling of _1D-ARs, the N- and C-terminal domains are not involved in this interaction, and that _1B-AR G protein coupling is not required. These observations may be relevant to many other Class I G protein-coupled receptors, where the functional consequences of heterodimerization are still poorly understood.

Received for publication, December 22, 2003 , and in revised form, January 12, 2004.

^* 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.

Supported by grants from the National Institutes of Health (NIH) and by a Distinguished Young Scholar in Medical Research Award from the W.M. Keck Foundation.

^¶ Supported by grants from the NIH.

To whom correspondence should be addressed: Dept. of Pharmacology, Emory University, Atlanta, GA 30322. Tel.: 404-727-0363; Fax: 404-727-0365; E-mail: chague{at}emory.edu.

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