Insulin stimulates phosphorylation of the β2-adrenergic receptor by the insulin receptor, creating a potent feedback inhibitor of its tyrosine kinase

Abstract

Insulin counterregulates catecholamine action at several levels, primarily in liver, fat, and adipose tissue. Herein we observe that expression of increased levels of β2-adrenergic receptor increasingly inhibits insulin-stimulated phosphorylation of its primary downstream substrates (IRS-1,2). In Chinese hamster ovary cells, the insulin receptor phosphorylates dominantly Tyr364 in the C-terminal cytoplasmic domain of the β-receptor. A Y364A mutant form of the β2-adrenergic, in contrast, loses it ability to inhibit insulin-stimulated phosphorylation of IRS-1,2. Upon phosphorylation, the C-terminal cytoplasmic domain of the β2-adrenergic receptor demonstrates a potent inhibitory feedback action that can block both insulin-stimulated autophosphorylation of the insulin receptor and phosphorylation of IRS-1,2 in NIH mouse 3T3-L1 adipocyte membranes. Studies in vitro with purified insulin receptor and the C-terminal cytoplasmic domain of the β2-adrenergic receptor demonstrate that the tyrosine-phosphorylated β-receptor domain is a potent counterregulatory inhibitor of the insulin receptor tyrosine kinase.