Ashby B, Daniel J L, Smith J B
Department of Pharmacology, Temple University Health Sciences Center, Philadelphia, Pennsylvania.
Hematol Oncol Clin North Am. 1990 Feb;4(1):1-26.
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.
血小板中刺激-反应偶联机制与引发反应的化合物一样复杂多样。血小板释放或合成的物质产生的反馈机制以及信号转导途径之间的“串扰”，使情况更加复杂。串扰的例子包括：肾上腺素通过G蛋白介导的机制抑制血小板腺苷酸环化酶，同时通过其他机制引起血小板聚集；cAMP抑制凝血酶刺激的二酰基甘油形成。尽管存在这些复杂性，但一些共同的线索已开始显现，例如G蛋白参与转导许多受体介导的过程、相对较少的第二信使途径的参与以及钙在许多导致血小板反应的事件中的作用，还有蛋白激酶在执行第二信使功能中的共同参与。后者为许多激动剂的作用提供了一种有用的检测方法，因为它们会导致特定蛋白质的磷酸化，而这可以通过放射自显影轻易检测到。事实上，在过去10年里，重点已从相对粗略的血小板功能测量（如聚集）转向对蛋白质磷酸化和钙释放等过程的精确、可量化测量，这些过程是血小板功能所涉及基本机制的指标，因此可作为这些过程的检测方法。另一方面，还有其他途径和调节因子有待发现，特别是关于肾上腺素的作用和磷脂酶A2的调节。此外，某些受体仍然难以捉摸，包括ADP和类花生酸的受体。凝血酶和组织蛋白酶G的作用机制涉及其蛋白水解活性，这仍然是一个谜。对第二信使功能的新见解与分子生物学技术的结合将使许多这些问题得到解决，为血栓栓塞性疾病的治疗提供新方法。
