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

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.