The tyrosine phosphorylation of GRK2 is responsible for activated D2R-mediated insulin resistance

Dopamine D 2 receptor (D 2 R) plays a key role in the regulation of glucose homeostasis by stimulating the secretion of many glucoregulatory hormones. Insulin resistance (IR) is associated with the pathogenesis of metabolic disorders which occurs when PI3K/Akt signaling pathway is downregulated. However, the potential involvement of D 2 R in insulin resistance remains unclear. In the present study, we investigated the regulation of glucose transport by D2-like receptors and discovered that activation of D 2 R, but not D 3 R or D 4 R, suppressed insulin-induced 2-DOG uptake and Glut4 membrane translocation in a GRK2- and Src-dependent manner. Further study revealed that activation of D 2 R inhibits insulin-induced phosphorylation of Akt at Thr308 and Ser473, which are hallmarks of its kinase activity, by increasing the interaction of tyrosine phosphorylated GRK2 with Akt and then preventing Akt from interacting with PDK1. Thus, this study demonstrates that Src mediated GRK2 tyrosine phosphorylation is an essential physiological event that mediates the roles of D 2 R in insulin resistance. • D2-like receptors were studied in correlation with their roles in insulin resistance. • D 2 R, not D 3 R or D 4 R, exerted negative effects on insulin-induced 2-DOG uptake and Glut4 translocation. • Tyrosine-phosphorylated GRK2 interacts with Akt, resulting in the suppression of insulin-induced Akt kinase activity after DA stimulation. • Activation of D 2 R mediated inhibition of insulin-induced interaction between PDK1 and Akt.