Journal
ENDOCRINOLOGY
Volume 146, Issue 1, Pages 450-457Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2004-0595
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Funding
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK025410, R01DK030111] Funding Source: NIH RePORTER
- NIDDK NIH HHS [DK25410, DK30111] Funding Source: Medline
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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.
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