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The 15-Amino Acid Motif of the C Terminus of the ß₂-Adrenergic Receptor Is Sufficient to Confer Insulin-Stimulated Counterregulation to the ß₁-Adrenergic Receptor

Department of Molecular Pharmacology (S.G., D.Y., E.S., C.C.M.), University Medical Center, State University of New York/Stony Brook, Stony Brook, New York 11794-8651; and Department of Physiology and Biophysics (H.-y.W.), Diabetes and Metabolic Diseases Research Program, University Medical Center, State University of New York/Stony Brook, Stony Brook, New York 11794-8661

Address all correspondence and requests for reprints to: Craig C. Malbon, Department of Pharmacology, Health Sciences Center, State University of New York/Stony Brook, Stony Brook, New York 11794-8651. E-mail craig{at}pharm.sunysb.edu.

Insulin counterregulates catecholamine action in part by inducing the sequestration of ß₂-adrenergic receptors. Although similar to agonist-induced sequestration, insulin-induced internalization of ß₂-adrenergic receptors operates through a distinct and better-understood cellular pathway. The effects of insulin treatment on the function and trafficking of both ß₁- and ß₂-adrenergic receptors were tested. The ß₂-adrenergic receptors were counterregulated and internalized in response to insulin. The ß₁-adrenergic receptors, in sharp contrast, are shown to be resistant to the ability of insulin to counterregulate function and induce receptor internalization. Using chimeric receptors composed of ß₁-/ß₂-adrenergic receptors in tandem with mutagenesis, we explored the role of the C-terminal cytoplasmic tail of the ß₂-adrenergic receptors for insulin-induced counterregulation. Substitution of the C-terminal cytoplasmic tail of the ß₂-adrenergic receptor on the ß₁-adrenergic receptor enabled the chimeric G protein-coupled receptor to be functionally and spatially regulated by insulin. Truncation of the ß₂-adrenergic receptor C-terminal cytoplasmic tail to a 15-amino acid motif harboring a potential Src homology 2-binding domain at Y350 and an Akt phosphorylation site at S345,346 was sufficient to enable receptor regulation by insulin.