Dual Mechanisms of Platelet Hormone Receptor Desensitization

Several different agonists, among them a-thrombin, platelet-activating factor, vasopressin, thromboxane Az, and endoperoxides, activate platelets to aggregate and secrete granular contents. Each of these agents is thought to act by inducing the turnover of inositol phospholipids and generating the second messenger molecules inositol 1,4,5-trisphosphate and 1,2-diacylglycerol. However, within minutes, the action of these agonists desensitizes. We have studied the characteristics of this desensitization process for the agonists mentioned above in an attempt to clarify the mechanisms involved. Our results show that two different pathways of desensitization exist, one that is mediated by protein kinase C and another that is independent of this enzyme. In addition, the contribution of these pathways to desensitization differs for the agonists studied. Our data suggest that partial agonists and strong agonists differ in the rate at which the primary response is desensitized rather than in their ability to couple to phospholipase C. Human platelets are activated by several different agonists acting on specific receptors (1). Included in the list of receptors are those for thrombin, thromboxane Az, endoperoxides, platelet-activating factor (PAF),' and vasopressin. One primary effect of receptor occupation is to induce the phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (2) to yield inositol 1,4,5-trisphosphate (IPS) (3-5) and 1,2-diacylglycerol ( 6 ) . These compounds activate the release of intracellular Ca2+ stores ( 3 ) and protein kinase C (7), respectively; this represents a major pathway for inducing subsequent platelet responses, such as aggregation and secretion.