Insulin induces IRS2-dependent and GRK2-mediated β₂AR internalization to attenuate βAR signaling in cardiomyocytes

The counter-regulatory effects of insulin and catecholamines on carbohydrate and lipid metabolism are well studied, whereas the details of insulin regulation of β adrenergic receptor (βAR) signaling pathway in heart remain unknown. Here, we characterize a novel signaling pathway of insulin receptor (IR) to G protein-coupled receptor kinase 2 (GRK2) in the heart. Insulin stimulates recruitment of GRK2 to β₂AR, which induces β₂AR phosphorylation at the GRK sites of serine 355/356 and subsequently β₂AR internalization. Insulin thereby suppresses βAR-induced cAMP-PKA activities and contractile response in neonatal and adult mouse cardiomyocytes. Deletion of insulin receptor substrate 2 (IRS2) disrupts the complex of IR and GRK2, which attenuates insulin-mediated β₂AR phosphorylation at the GRK sites and β₂AR internalization, and the counter-regulation effects of insulin on βAR signaling. These data indicate the requirements of IRS2 and GRK2 for insulin to stimulate counter-regulation of βAR via β₂AR phosphorylation and internalization in cardiomyocytes.