The 15-amino acid motif of the C terminus of the β2-adrenergic receptor is sufficient to confer insulin-stimulated counterregulation to the β1-adrenergic receptor

Insulin counterregulates catecholamine action in part by inducing the sequestration of beta(2)-adrenergic receptors. Although similar to agonist-induced sequestration, insulin-induced internalization of beta(2)-adrenergic receptors operates through a distinct and better-understood cellular pathway. The effects of insulin treatment on the function and trafficking of both beta(1)- and beta(2)-adrenergic receptors were tested. The beta(2)-adrenergic receptors were counterregulated and internalized in response to insulin. The beta(1)-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 beta(1)-/beta(2)-adrenergic receptors in tandem with mutagenesis, we explored the role of the C-terminal cytoplasmic tail of the beta(2)-adrenergic receptors for insulin-induced counterregulation. Substitution of the C-terminal cytoplasmic tail of the beta(2)-adrenergic receptor on the beta(1)-adrenergic receptor enabled the chimeric G protein-coupled receptor to be functionally and spatially regulated by insulin. Truncation of the beta(2)-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.