Mechanisms of Platelet Activation and Inhibition

Abstract

Mechanisms of stimulus-response coupling in platelets are as complex and varied as the compounds that elicit the responses. The complexities are compounded by feedback mechanisms from substances released or synthesized by platelets as well as by "cross-talk" between signal transduction pathways. Examples of cross-talk include the ability of epinephrine to inhibit platelet adenylate cyclase through a G protein-mediated mechanism while causing platelet aggregation by some other mechanism and the ability of cAMP to inhibit thrombin-stimulated diacylglycerol formation. Despite the complexities, certain common threads are beginning to emerge, such as the involvement of G proteins in transducing many receptor-mediated processes, the involvement of relatively few second messenger pathways and the role of calcium in many of events leading to platelet responses, and the common involvement of protein kinases in carrying out second messenger function. The latter offers a useful assay for the effect of many agonists because they lead to the phosphorylation of specific proteins that can readily be detected by radioautography. Indeed, the emphasis has shifted in the past 10 years from relatively crude measurements of platelet function such as aggregation to precise, quantifiable measurement of processes such as protein phosphorylation and calcium release, which are indicators of the fundamental mechanisms involved in platelet function and thus serve as assays of these processes. On the other hand, there are other pathways and regulators yet to be discovered, notably regarding the action of epinephrine and the regulation of phospholipase A2. In addition, certain receptors remain elusive, including those for ADP and eicosanoids. The mechanisms of action of thrombin and cathepsin G, which involve their proteolytic activities, also remain an enigma. The combination of new insights into second messenger function and the techniques of molecular biology will allow many of these problems to be resolved, providing new approaches to therapy of thromboembolic disorders.