Kahn M L, Zheng Y W, Huang W, Bigornia V, Zeng D, Moff S, Farese R V, Tam C, Coughlin S R
Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco 94143-0130, USA.
Nature. 1998 Aug 13;394(6694):690-4. doi: 10.1038/29325.
Platelet-dependent arterial thrombosis triggers most heart attacks and strokes. Because the coagulation protease thrombin is the most potent activator of platelets, identification of the platelet receptors for thrombin is critical for understanding thrombosis and haemostasis. Protease-activated receptor-1 (PAR1) is important for activation of human platelets by thrombin, but plays no apparent role in mouse platelet activation. PAR3 is a thrombin receptor that is expressed in mouse megakaryocytes. Here we report that thrombin responses in platelets from PAR3-deficient mice were markedly delayed and diminished but not absent. We have also identified PAR4, a new thrombin-activated receptor. PAR4 messenger RNA was detected in mouse megakaryocytes and a PAR4-activating peptide caused secretion and aggregation of PAR3-deficient mouse platelets. Thus PAR3 is necessary for normal thrombin responses in mouse platelets, but a second PAR4-mediated mechanism for thrombin signalling exists. Studies with PAR-activating peptides suggest that PAR4 also functions in human platelets, which implies that an analogous dual-receptor system also operates in humans. The identification of a two-receptor system for platelet activation by thrombin has important implications for the development of antithrombotic therapies.
血小板依赖性动脉血栓形成引发了大多数心脏病发作和中风。由于凝血蛋白酶凝血酶是血小板最有效的激活剂，因此确定凝血酶的血小板受体对于理解血栓形成和止血至关重要。蛋白酶激活受体-1（PAR1）对于凝血酶激活人血小板很重要，但在小鼠血小板激活中没有明显作用。PAR3是一种在小鼠巨核细胞中表达的凝血酶受体。我们在此报告，PAR3缺陷小鼠血小板中的凝血酶反应明显延迟且减弱，但并非不存在。我们还鉴定出一种新的凝血酶激活受体PAR4。在小鼠巨核细胞中检测到PAR4信使核糖核酸，并且一种PAR4激活肽可导致PAR3缺陷小鼠血小板的分泌和聚集。因此，PAR3对于小鼠血小板中的正常凝血酶反应是必需的，但存在第二种由PAR4介导的凝血酶信号传导机制。对PAR激活肽的研究表明，PAR4在人血小板中也起作用，这意味着类似的双受体系统在人类中也起作用。凝血酶激活血小板的双受体系统的鉴定对于抗血栓治疗的发展具有重要意义。
