Abstract:Previous studies have shown that while vasopressin and angiotensin I1 are markedly more effective than norepinephrine and prostaglandin FZa in eliciting an acute elevation of inositol 1.4,5-trisphosphate (IP,), norepinephrine and prostaglandin F2u produce larger enhancement of DNA synthesis. This suggests that the initial activation of phosphoinositide-specific phospholipase C is not a common factor for the growth response to these agonists, but does not exclude a role of the integral of phospholipase C activity over a prolonged part of the prereplicative period, during which agonistspecific changes in responsiveness might occur. We show that vasopressin and angiotensin 11 also cause a prolonged elevation of cellular IP, levels, which remain elevated for at least 60 min., while norepinephrine and prostaglandin F2a elevate IP3 levels slightly and transiently. For vasopressin the dose-effect curves for IP, accumulation and stimulation of DNA synthesis were closely parallel, while this was not the case for angiotensin 11, norepinephrine, or prostaglandin Fza. After cultivation of the hepatocytes, hormone-stimulated IP3 accumulation rapidly declined. particularly in response to norepinephrine and prostaglandin F2=. When the IP, response to norepinephrine and prostaglandin F2= was completely down-regulated, these agonists still enhanced the DNA synthesis. These results suggest that other mechanisms in addition to IP3 accumulation and Ca2+ release are likely to be involved in the growth stimulatory effects of the Ca2+-mobilizing agonists studied here, in particular for angiotensin 11, norepinephrine, and prostaglandin F2,.Activation of phosphoinositide-specific phospholipase C, resulting in breakdown of phosphatidylinositol4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol, is one of the early events following interaction of many mitogenic agents with their receptors (Berridge 1993). IP3 elevates cytosolic free CaZ+, which seems to be crucial in the control of several specific points in the cell cycle (Berridge 1995), while diacylglycerol activates protein kinase C, which is also involved in growth-promoting mechanisms (Nishizuka 1995). This and other evidence (Whitman & Cantley 1988;Noh et al. 1995) strongly implicate activation of phosphoinositide-specific phospholipase C in mitogenic signaling. Various Ca2+-mobilizing agents that activate phosphoinositide-specific phospholipase C through G protein-coupled receptors stimulate cell proliferation (van Biesen et al. 1996; Post & Brown 1996). Many of these agonists also exert various other effects in the cell, such as stimulation of phospholipase D (Exton 1994; Nishizuka 1995), phosphoinositide 3-kinase (Nishioka et al. 1995;Hu et al. 1996) or tyrosine kinases (Watanabe et al. 1994; Gonzalez-Espinosa & Garcia-Sainz 1995), and it is not fully clarified whether these effects occur downstream or independently of phosphoinositide-specific phospholipase C.Norepinephrine, vasopressin, angiotensin 11, and prostaglandin Fzu activate phosphoin...