Puri R N, Colman R W
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Crit Rev Biochem Mol Biol. 1997;32(6):437-502. doi: 10.3109/10409239709082000.
Platelet activation is central to the pathogenesis of hemostasis and arterial thrombosis. Platelet aggregation plays a major role in acute coronary artery diseases, myocardial infarction, unstable angina, and stroke. ADP is the first known and an important agonist for platelet aggregation. ADP not only causes primary aggregation of platelets but is also responsible for the secondary aggregation induced by ADP and other agonists. ADP also induces platelet shape change, secretion from storage granules, influx and intracellular mobilization of Ca2+, and inhibition of stimulated adenylyl cyclase activity. The ADP-receptor protein mediating ADP-induced platelet responses has neither been purified nor cloned. Therefore, signal transduction mechanisms underlying ADP-induced platelet responses either remain uncertain or less well understood. Recent contributions from chemists, biochemists, cell biologists, pharmacologists, molecular biologists, and clinical investigators have added considerably to and enhanced our knowledge of ADP-induced platelet responses. Although considerable efforts have been directed toward identifying and cloning the ADP-receptor, these have not been completely successful or without controversy. Considerable progress has been made toward understanding the mechanisms of ADP-induced platelet responses but disagreements persist. New drugs that do not mimic ADP have been found to inhibit fairly selectively ADP-induced platelet activation ex vivo. Drugs that mimic ADP and selectively act at the platelet ADP-receptor have been designed, synthesized, and evaluated for their therapeutic efficacy to block selectively ADP-induced platelet responses. This review examines in detail the developments that have taken place to identify the ADP-receptor protein and to better understand mechanisms underlying ADP-induced platelet responses to develop strategies for designing innovative drugs that block ADP-induced platelet responses by acting selectively at the ADP-receptor and/or by selectively interfering with components of ADP-induced platelet activation mechanisms.
血小板活化是止血和动脉血栓形成发病机制的核心。血小板聚集在急性冠状动脉疾病、心肌梗死、不稳定型心绞痛和中风中起主要作用。ADP是已知的第一种也是血小板聚集的重要激动剂。ADP不仅引起血小板的初级聚集，还负责由ADP和其他激动剂诱导的次级聚集。ADP还诱导血小板形状改变、储存颗粒分泌、Ca2+内流和细胞内动员，以及抑制受刺激的腺苷酸环化酶活性。介导ADP诱导的血小板反应的ADP受体蛋白既未被纯化也未被克隆。因此，ADP诱导的血小板反应的信号转导机制要么仍然不确定，要么了解较少。化学家、生物化学家、细胞生物学家、药理学家、分子生物学家和临床研究人员最近的贡献大大增加并增强了我们对ADP诱导的血小板反应的认识。尽管已经投入了大量努力来鉴定和克隆ADP受体，但这些努力尚未完全成功或没有争议。在理解ADP诱导的血小板反应机制方面已经取得了相当大的进展，但分歧仍然存在。已发现不模拟ADP的新药在体外能相当选择性地抑制ADP诱导的血小板活化。模拟ADP并选择性作用于血小板ADP受体的药物已被设计、合成并评估其阻断ADP诱导的血小板反应的治疗效果。这篇综述详细探讨了在鉴定ADP受体蛋白以及更好地理解ADP诱导的血小板反应机制方面所取得的进展，以便制定策略来设计创新药物，这些药物通过选择性作用于ADP受体和/或通过选择性干扰ADP诱导的血小板活化机制的组成部分来阻断ADP诱导的血小板反应。
