Nurden A T, Nurden P
URA 1464 CNRS, Hôpital Cardiologique, Pessac, France.
Baillieres Clin Haematol. 1993 Sep;6(3):653-90. doi: 10.1016/s0950-3536(05)80193-3.
This review concerns our understanding of the molecular basis of platelet function in haemostasis. In particular, we indicate how research into platelet membrane glycoprotein (GP) receptors is yielding vital information on the mechanisms of platelet adhesion and aggregation. These receptors, nearly always complexes of two or more subunits, are now known to belong to distinct gene families, some of which are unique to platelets while others are widely distributed in mammalian tissues. GP Ib-IX complexes are responsible for the high-shear-rate-dependent adhesion of platelets to von Willebrand factor (vWF) exposed within the subendothelium of damaged vessels. Other adhesion receptors include members of the VLA subclass of the integrin family: VLA-2, VLA-5 and VLA-6, which mediate platelet adhesion to collagen, fibronectin and laminin, respectively. Platelet aggregation is initiated by distinct populations of receptors specific for each physiological agonist. Many of these receptors, including the highly important and recently cloned thrombin receptor, have seven transmembrane domains and possess highly selective agonist-binding determinants. Finally, we highlight platelet aggregation and the role of GP IIb-IIIa complexes which, following platelet activation, bind fibrinogen and other adhesive proteins. The latter, through being polyvalent for GP IIb-IIIa, then form the bridges linking adjoining platelets. The 'ligand-binding pocket' of GP IIb-IIIa contains at least three sequences essential for ligand binding; fibrinogen also binds to the activated complex through identified domains, one of which, the Arg-Gly-Asp (RGD) sequence, is also found in vWF and the other adhesive proteins able to support platelet aggregation. Finally, we further describe how these, and other glycoproteins in both surface and internal membrane systems, constitute a complex receptor network capable of translocation and reorganization after platelet activation. In cardiovascular disease, platelets accumulate within arteries whose luminal surface has been modified through atherosclerosis. Recent molecular advances are yielding exciting opportunities for the development of new, and more powerful, drugs acting as specific inhibitors of thrombotic processes.
本综述涉及我们对止血过程中血小板功能分子基础的理解。特别是，我们指出了对血小板膜糖蛋白（GP）受体的研究如何为血小板黏附和聚集机制提供重要信息。这些受体几乎总是由两个或更多亚基组成的复合物，现在已知它们属于不同的基因家族，其中一些是血小板特有的，而另一些则广泛分布于哺乳动物组织中。GP Ib-IX复合物负责血小板在高剪切速率下与受损血管内皮下暴露的血管性血友病因子（vWF）的黏附。其他黏附受体包括整合素家族VLA亚类的成员：VLA-2、VLA-5和VLA-6，它们分别介导血小板与胶原蛋白、纤连蛋白和层粘连蛋白的黏附。血小板聚集由针对每种生理激动剂的不同受体群体引发。这些受体中的许多，包括非常重要且最近克隆的凝血酶受体，都有七个跨膜结构域，并具有高度选择性的激动剂结合决定簇。最后，我们强调血小板聚集以及GP IIb-IIIa复合物 的作用，血小板激活后，GP IIb-IIIa复合物会结合纤维蛋白原和其他黏附蛋白。后者通过对GP IIb-IIIa具有多价性，进而形成连接相邻血小板的桥梁。GP IIb-IIIa的“配体结合口袋”包含至少三个对配体结合至关重要的序列；纤维蛋白原也通过已确定的结构域与活化复合物结合，其中一个结构域，即精氨酸-甘氨酸-天冬氨酸（RGD）序列，也存在于vWF和其他能够支持血小板聚集的黏附蛋白中。最后，我们进一步描述这些以及表面和内膜系统中的其他糖蛋白如何构成一个复杂的受体网络，该网络在血小板激活后能够进行易位和重组。在心血管疾病中，血小板在动脉腔内表面因动脉粥样硬化而发生改变的动脉中聚集。最近的分子进展为开发作为血栓形成过程特异性抑制剂的新型、更强大的药物带来了令人兴奋的机会。
