Insulin-like growth factor-I induces alpha-1B adrenoceptor esensitization, phosphorylation and internalization.
Tzindilu Molina-Muñoz, Maria Teresa Romero-Avila and Adolfo Garcia-Sainz*
Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, MEXICO. Apartado postal 70-248, Mexico, DF, 04510.
agracia@ifc.unam.mx
Insulin-like growth factor-I (IGF-I) induces alpha-1B-adrenoceptor phosphorylation associated to receptor desensitization. The effect of IGF-I was markedly decreased by pertussis toxin suggesting a role of pertussis toxin-sensitive G proteins. Transfection of the carboxyl terminus of the ß-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 PI3K and PKC also blocked this effect. 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 IGF-I induced alpha-1B-adrenoceptor desensitization is associated to adrenoceptor internalization. The following sequence of events are suggested:(i) stimulation of IGF-I receptors activate pertussis toxin-sensitive G proteins; (ii) this activates metalloproteinases, which catalyze heparin binding-EGF shedding, and transactivation of EGF receptors and (iii) dissociated Gßy subunits and phosphotyrosine residues stimulate PI3K activity, which leads to activation of PKC, resulting in ∞1B-adrenoceptor phosphorylation, desensitization and internalization. Acknowledgement: This research was supported by Grants from DGAPA (IN200206) and CONACyT (45837-Q).
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