Insulin-like growth factor-I (IGF-I) induces _1B-adrenoceptor phosphorylation. The effect of IGF-I was rapid and transient, reaching near-maximal values at 10 min and decreasing after 30 min; it was observed at low IGF-I concentrations (EC₅₀ 10 ng/ml) and was associated to receptor desensitization as evidenced by a decreased _1B-adrenergic effect on intracellular calcium and production of inositol phosphates. The effect of IGF-I was markedly decreased in cells treated with pertussis toxin suggesting involvement of pertussis toxin-sensitive G proteins. Transfection of the carboxyl terminus of the -adrenergic receptor kinase or the p85 mutant of phosphoinositide 3-kinase markedly decreased the _1B-adrenoceptor phosphorylation induced by IGF-I without decreasing the receptor phosphorylation induced by noradrenaline. Inhibitors of phosphoinositide 3-kinase and PKC blocked IGF-I-induced _1B-adrenoceptor phosphorylation. In addition, it was observed that AG1478, an inhibitor of the EGF receptor kinase and BB-94, a metalloproteinase inhibitor, also diminished IGF-I-induced adrenoceptor phosphorylation.

The data clearly show that IGF-I triggers a complex signaling pathway, which leads to the phosphorylation and desensitization of a serpentine G protein-coupled receptor suggesting the following hypothetical model: a) stimulation of IGF-I receptors activate pertussis toxin-sensitive G proteins; b) the growth factor action activates metalloproteinases, which catalyze heparin binding-EGF shedding, and transactivation of EGF receptors and c) dissociated G subunits and phosphotyrosine residues seem to trigger phosphoinositide 3-kinase activity, which leads to activation of protein kinase C resulting in _1B-adrenoceptor phosphorylation and desensitization.