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CELLULAR AND MOLECULAR

_2C-Adrenergic Receptors Exhibit Enhanced Surface Expression and Signaling upon Association with ₂-Adrenergic Receptors

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia

The _2C-adrenergic receptor (_2CAR) is known to be poorly trafficked to the cell surface when expressed in a variety of cell types. We tested the hypothesis that the surface expression and signaling of _2CAR might be enhanced by heterodimerization with other G protein-coupled receptors (GPCRs). Cotransfection of _2CAR with more than 25 related GPCRs revealed that only coexpression with the ₂-adrenergic receptor (₂AR) increased the surface localization of _2CAR in human embryonic kidney-293 cells. Coimmunoprecipitation of _2CAR with ₂AR confirmed a physical interaction between the two receptors. Confocal microscopy studies demonstrated that _2CAR expressed alone was mainly intracellular, whereas _2CAR coexpressed with ₂AR was predominantly localized to the plasma membrane. Ligand binding studies revealed a significant increase in _2CAR binding sites upon coexpression with ₂AR, with no apparent change in affinity for ₂AR ligands. Functional assays with the ₂AR-specific agonist brimonidine (UK 14,304) revealed that coexpression of ₂AR with _2CAR enhanced _2CAR-mediated activation of extracellular signal-regulated kinase 1/2. Furthermore, analyses of agonist-promoted receptor endocytosis demonstrated enhanced _2CAR internalization in response to ₂AR agonists when _2CAR and ₂AR were coexpressed. In addition, substantial cointernalization of _2CAR in response to AR agonists was observed when _2CAR was coexpressed with ₂AR. These data reveal that _2CAR can interact with ₂AR in cells in a manner that regulates _2CAR surface expression, internalization, and functionality.

Address correspondence to: Dr. Randy A. Hall, Department of Pharmacology, Emory University School of Medicine, 5113 Rollins Research Center, 1510 Clifton Rd., Atlanta, GA 30322. E-mail: rhall{at}pharm.emory.edu

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