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Received for publication October 20, 2004.
Revised December 15, 2004.
Accepted for publication December 16, 2004.
The alpha-1D-adrenergic receptor (alpha1D-AR) is a G protein-coupled receptor (GPCR) that is poorly trafficked to the cell surface and largely non-functional when heterologously expressed by itself in a variety of cell types. We screened a library of approximately 30 other group I GPCRs in a quantitative luminometer assay for the ability to promote alpha1D-AR cell surface expression. Strikingly, these screens revealed only two receptors capable of inducing robust increases in the amount of alpha1D-AR at the cell surface: alpha1B-AR and beta2-AR. Confocal imaging confirmed that co-expression with beta2-AR resulted in translocation of alpha1D-AR from intracellular sites to the plasma membrane. Additionally, co-immunoprecipitation studies demonstrated that alpha1D-AR and beta2-AR specifically interact to form heterodimers when co-expressed in HEK-293 cells. Ligand binding studies revealed an increase in total alpha1D-AR binding sites upon co-expression with beta2-AR, but no apparent effect on the pharmacological properties of the receptors. In functional studies, co-expression with beta2-AR significantly enhanced the coupling of alpha1D-AR to norepinephrine-stimulated Ca2+ mobilization. Heterodimerization of beta2-AR with alpha1D-AR also conferred the ability of alpha1D-AR to co-internalize upon beta2-AR agonist stimulation, revealing a novel mechanism by which these different adrenergic receptor subtypes may regulate each other's activity. These findings demonstrate that the selective association of alpha1D-AR with other receptors is crucial for receptor surface expression and function, and also shed light on a novel mechanism of cross-talk between alpha1- and beta2-ARs that is mediated through heterodimerization and cross-internalization.
Key words:
adrenoceptor, brain, cardiovascular, dimerization, endocytosis, oligomerization
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