title: Beta -Arrestin 1 down-regulation after insulin treatment is associated with supersensitization of beta 2 adrenergic receptor Galpha s signaling in 3T3-L1 adipocytes.
abstract: beta-Arrestin 1 is required for internalization and mitogen-activated protein (MAP) kinase activation by the beta2 adrenergic receptor (beta2AR). Our previous studies have shown that chronic insulin treatment down-regulates cellular beta-arrestin 1 levels, leading to a marked impairment in G protein-coupled receptor and insulin-like growth factor-1 receptor-mediated MAP kinase and mitogenic signaling. In this study, we show that chronic insulin-treated, beta-arrestin 1depleted 3T3-L1 adipocytes display (i) increased isoproterenol-induced cAMP generation (53 +/- 38% at 1.5 min, 25 +/- 19% at 5 min, 63 +/- 14% at 30 min, and 59 +/- 2% at 60 min), a Galpha(s)-associated pathway; (ii) impaired isoproterenol-induced beta2AR internalization (reduced by 98 +/- 4%), which is required for MAP kinase signaling, a Galpha(i)-associated pathway; and (iii) increased beta-arrestin 1 phosphorylation at Ser-412. Taken together, these findings represent a hitherto unknown mechanism (degradation and phosphorylation of beta-arrestin, whereby the activation of the insulin receptor, belonging to the family of receptor tyrosine kinases, causes supersensitization of Galpha(s)-associated signaling and inhibition of Galpha(i)-associated signaling by the beta2AR, a prototypical G protein-coupled receptor.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla 92093, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hupfeld
authors.forename: Stephane
authors.initials: S
authors.lastname: Dalle
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D019390:Arrestins / Q000187:drug effects / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology*; D007328:Insulin / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605255:Arrb1 protein, mouse; D019390:Arrestins; D007328:Insulin; D018343:Receptors, Adrenergic, beta-2; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D005576:Colforsin; D000242:Cyclic AMP; D020962:Heterotrimeric GTP-Binding Proteins; D007545:Isoproterenol