Smyth Susan S, Woulfe Donna S, Weitz Jeffrey I, Gachet Christian, Conley Pamela B, Goodman Shaun G, Roe Matthew T, Kuliopulos Athan, Moliterno David J, French Patricia A, Steinhubl Steven R, Becker Richard C
Veterans Affairs Medical Center, Department of Medicine, Physiology, and Pharmacology, University of Kentucky, Lexington, KY, USA.
Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):449-57. doi: 10.1161/ATVBAHA.108.176388. Epub 2008 Nov 20.
Platelet G protein-coupled receptors (GPCRs) initiate and reinforce platelet activation and thrombus formation. The clinical utility of antagonists of the P2Y(12) receptor for ADP suggests that other GPCRs and their intracellular signaling pathways may represent viable targets for novel antiplatelet agents. For example, thrombin stimulation of platelets is mediated by 2 protease-activated receptors (PARs), PAR-1 and PAR-4. Signaling downstream of PAR-1 or PAR-4 activates phospholipase C and protein kinase C and causes autoamplification by production of thromboxane A(2), release of ADP, and generation of more thrombin. In addition to ADP receptors, thrombin and thromboxane A(2) receptors and their downstream effectors-including phosphoinositol-3 kinase, Rap1b, talin, and kindlin-are promising targets for new antiplatelet agents. The mechanistic rationale and available clinical data for drugs targeting disruption of these signaling pathways are discussed. The identification and development of new agents directed against specific platelet signaling pathways may offer an advantage in preventing thrombotic events while minimizing bleeding risk.
血小板G蛋白偶联受体（GPCRs）启动并加强血小板活化和血栓形成。P2Y(12)受体拮抗剂对ADP的临床效用表明，其他GPCRs及其细胞内信号通路可能是新型抗血小板药物的可行靶点。例如，凝血酶对血小板的刺激由2种蛋白酶激活受体（PARs），即PAR-1和PAR-4介导。PAR-1或PAR-4下游的信号传导激活磷脂酶C和蛋白激酶C，并通过血栓素A(2)的产生、ADP的释放以及更多凝血酶的生成导致自身放大。除了ADP受体外，凝血酶和血栓素A(2)受体及其下游效应器——包括磷酸肌醇-3激酶、Rap1b、踝蛋白和纽带蛋白——都是新型抗血小板药物的有前景的靶点。本文讨论了针对这些信号通路破坏的药物的作用机制原理和现有临床数据。针对特定血小板信号通路的新型药物的鉴定和开发可能在预防血栓形成事件同时将出血风险降至最低方面具有优势。
