TY - JOUR T1 - α<sub>2C</sub>-Adrenergic Receptors Exhibit Enhanced Surface Expression and Signaling upon Association with β<sub>2</sub>-Adrenergic Receptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 974 LP - 981 DO - 10.1124/jpet.106.106526 VL - 318 IS - 3 AU - Steven C. Prinster AU - Tomas G. Holmqvist AU - Randy A. Hall Y1 - 2006/09/01 UR - http://jpet.aspetjournals.org/content/318/3/974.abstract N2 - The α2C-adrenergic receptor (α2CAR) 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 α2CAR might be enhanced by heterodimerization with other G protein-coupled receptors (GPCRs). Cotransfection of α2CAR with more than 25 related GPCRs revealed that only coexpression with the β2-adrenergic receptor (β2AR) increased the surface localization of α2CAR in human embryonic kidney-293 cells. Coimmunoprecipitation of α2CAR with β2AR confirmed a physical interaction between the two receptors. Confocal microscopy studies demonstrated that α2CAR expressed alone was mainly intracellular, whereas α2CAR coexpressed with β2AR was predominantly localized to the plasma membrane. Ligand binding studies revealed a significant increase in α2CAR binding sites upon coexpression with β2AR, with no apparent change in affinity for α2AR ligands. Functional assays with the α2AR-specific agonist brimonidine (UK 14,304) revealed that coexpression of β2AR with α2CAR enhanced α2CAR-mediated activation of extracellular signal-regulated kinase 1/2. Furthermore, analyses of agonist-promoted receptor endocytosis demonstrated enhanced α2CAR internalization in response to α2AR agonists when α2CAR and β2AR were coexpressed. In addition, substantial cointernalization of α2CAR in response to βAR agonists was observed when α2CAR was coexpressed with β2AR. These data reveal that α2CAR can interact with β2AR in cells in a manner that regulates α2CAR surface expression, internalization, and functionality. The American Society for Pharmacology and Experimental Therapeutics ER -