Insulin and insulin-like growth factor I receptors utilize different G protein signaling components

We examined the role of heterotrimeric G protein signaling components in in sulin and insulin-like growth factor I (IGF-I) action. In HIRcB cells and i n 3T3L1 adipocytes, treatment with the G alpha (i) inhibitor (pertussis tox in) or microinjection of the G beta gamma inhibitor (glutathione S-transfer ase-beta ARK) inhibited IGF-I and lysophosphatidic acid-stimulated mitogene sis but had no effect on epidermal growth factor (EGF) or insulin action. I n basal state, G alpha (i) and G beta were associated with the IGF-I recept or (IGF-IR), and after ligand stimulation the association of IGF-IR with G alpha (1) increased concomitantly with a decrease in G beta association. No association of Ga-i was found with either the insulin or EGF receptor. Mic roinjection of anti-beta -arrestin-1 antibody specifically inhibited IGF-I mitogenic action but had no effect on EGF or insulin action. beta -Arrestin -1 was associated with the receptors for IGF-I, insulin, and EGF in a ligan d-dependent manner. We demonstrated that G alpha (i), beta gamma subunits, and beta -arrestin-1 all play a critical role in IGF-I mitogenic signaling. In contrast, neither metabolic, such as GLUT4 translocation, nor mitogenic signaling by insulin is dependent on these protein components. These resul ts suggest that insulin receptors and IGF-IRs can function as G protein-cou pled receptors and engage different G protein partners for downstream signa ling.