We have reported that fMLP-induced activation of pertussis toxin-sensitive GTP-binding proteins in THP-1 cells potentiates the insulin-induced accumulation of PtdIns(3,4,5)P 3 , a product of phosphoinositide 3-kinase. The synergism in PtdIns(3,4,5)P 3 accumulation was observed in Chinese hamster ovary cells expressing both insulin and fMLP receptors. In rat adipocytes, which represent the physiological target cells of insulin, receptor-mediated activation of GTP-binding protein by adenosine and prostaglandin E 2 potentiated the insulin-induced PtdIns(3,4,5)P 3 accumulation. In cell-free systems, the activity of the p85/p110β subtype of phosphoinositide 3-kinase was, while that of p85/p110α was not, stimulated by the βγ subunits of the GTP-binding proteins. We propose here a hypothesis that the p85/p110β subtype is under the control of both the insulin receptors and the GTP-binding protein-coupled receptors in intact cell systems.