Kinin signal transduction: role of phosphoinositides and eicosanoids

Kinins elicit prostaglandin and inositol phosphate production in 3T3 fibroblasts through stimulation of B2 receptors. Prostaglandin synthesis is maximum by 5 min, whereas inositol phosphate production continues for longer than 30 min. Prostaglandin synthesis is stimulated by phospholipase A2, which releases arachidonate from phospholipids, whereas a phosphatidylinositol-specific phospholipase C catalyzes formation of equimolar amounts of inositol phosphate and diacylglycerol. Stimulation of these two second-messenger systems occurs through independent pathways: (a) dexamethasone inhibits prostaglandin formation by inhibiting phospholipase A2, and, to a lesser degree, cyclooxygenase, but is without effect on inositol phosphate production; (b) neomycin inhibits inositol phosphate production without affecting prostaglandin synthesis; (c) phorbol esters inhibit inositol phosphate production while augmenting prostaglandin synthesis; and (d) indomethacin inhibits prostaglandin synthesis but does not affect inositol phosphate production. At later times (greater than 10 min), the two pathways interact. Stimulation with one agonist to increase diacylglycerol results in augmentation of prostaglandin synthesis in response to a second agonist. Inositol phosphates cause release of calcium from intracellular stores. Prostaglandins stimulate (by binding to their own receptors) adenylate cyclase to increase cAMP. Additionally, prostaglandins increase intracellular free calcium by increasing influx of extracellular calcium. Both inositol phosphates and prostaglandins play roles in mitogenesis in these cells.