The 15-amino acid motif of the C terminus of the beta2-adrenergic receptor is sufficient to confer insulin-stimulated counterregulation to the beta1-adrenergic receptor.
Insulin counterregulates catecholamine action in part by inducing the sequestration of beta2-adrenergic receptors. Although similar to agonist-induced sequestration, insulin-induced internalization of beta2-adrenergic receptors operates through a distinct and better-understood cellular pathway. The effects of insulin treatment on the function and trafficking of both beta1- and beta2-adrenergic receptors were tested. The beta2-adrenergic receptors were counterregulated and internalized in response to insulin. The beta1-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 beta1-/beta2-adrenergic receptors in tandem with mutagenesis, we explored the role of the C-terminal cytoplasmic tail of the beta2-adrenergic receptors for insulin-induced counterregulation. Substitution of the C-terminal cytoplasmic tail of the beta2-adrenergic receptor on the beta1-adrenergic receptor enabled the chimeric G protein-coupled receptor to be functionally and spatially regulated by insulin. Truncation of the beta2-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.
Gavi
Shai
S
Department of Pharmacology, University Medical Center, State University of New York/Stony Brook, Stony Brook, New York 11794-8651, USA.
Yin
Dezhong
D
Shumay
Elena
E
Wang
Hsien-Yu
HY
Malbon
Craig C
CC
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D020816:Amino Acid Motifs; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D018613:Microscopy, Confocal; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics* / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics
D000318:Adrenergic beta-Agonists; D007328:Insulin; D011518:Proto-Oncogene Proteins; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; D000242:Cyclic AMP; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D007545:Isoproterenol