Opposite Effects of Prostaglandins on Human Platelets Mediated by Distinct Protein Kinases

A wide variety of hormones initiate their effects on target cells by binding to specific cell-surface receptors. There appear to be two major cell-surface-receptor mechanisms operative in mediating the effects of hormones on intracellular processes. Many hormones interact with plasma membrane-bound receptors to activate the adenylate cyclase to increase the production of cAMP and thus activate a cAMP-dependent protein kinase. ¹ Numerous other extracellular messengers stimulate the inositol-phospholipid breakdown by a phospholipase C mechanism. ² One of the primary products of phosphatidylinositol turnover is diacylglycerol, which serves as a messenger of this hormonal stimulation to activate a Ca/ phospholipid-dependent enzyme, protein kinase C. ³ , Diacylglycerol greatly increases the affinity of protein kinase C for Ca²⁺, and thereby renders this enzyme fully active without a net increase in the Ca²⁺ concentration. ⁵ Thus, the receptor-mediated activation of this protein kinase is biologically independent of Ca²⁺ because its Ca²⁺ sensitivity is modulated. In many cell types, including the human platelet, activation of protein kinase C appears to be a prerequisite requirement, and acts synergistically with Ca²⁺ for eliciting full activation of cellular functions. ⁵ ,6 The proposed pathway of such a signal transduction is outlined in Figure 1. Recently, it was found that active tumor-promoting phorbol esters such as 12-0-tetradecanoylphorbol-13-acetate (TPA) intercalate into the membrane, substitute for diacylglycerol, and activate protein kinase C directly. ⁷