Role of the thrombin receptor In development and evidence for a second receptor
Role of the thrombin receptor In development and evidence for a second receptor
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DOI：
10.1038/381516a0
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发表时间：
1996-06-06
期刊：
影响因子：
64.8
通讯作者：
Coughlin, SR
中科院分区：
文献类型：
--
作者：
Connolly, AJ;Ishihara, H;Coughlin, SR
凝血酶是一种在血管损伤部位产生的凝血蛋白酶，可激活血小板、内皮细胞、白细胞和间充质细胞（1，2）。G蛋白偶联受体被凝血酶蛋白水解激活（3），是药物开发的目标，旨在阻断血栓形成，炎症和增殖。在这里，我们表明，虽然破坏小鼠凝血酶受体（tr）基因导致大约一半的tr（-/-）胚胎在胚胎第9-10天死亡，一半存活成为没有出血素质的大体正常的成年小鼠。引人注目的是，tr（-/-）血小板对凝血酶反应强烈，而tr（-/-）成纤维细胞失去了对凝血酶反应的能力。我们得出结论，凝血酶受体在胚胎发育中起着意想不到的作用，这表明“凝血”蛋白酶本身可能具有新的功能。此外，存在第二种血小板凝血酶受体，并且不同的凝血酶受体具有组织特异性作用。这可能允许开发将选择性地阻断凝血酶的不同细胞作用的疗法。
THROMBIN, a coagulation protease generated at sites of vascular injury, activates platelets, endothelial cells, leukocytes and mesenchymal cells(1,2). A G-protein-coupled receptor that is proteolytically activated by thrombin(3) is a target for drug development aimed at blocking thrombosis, inflammation and proliferation. Here we show that although disruption of the thrombin-receptor (tr) gene in mice causes about half the tr(-/-) embryos to die at embryonic day 9-10, half survive to become grossly normal adult mice with no bleeding diathesis. Strikingly, tr(-/-) platelets respond strongly to thrombin, whereas tr(-/-) fibroblasts lose their ability to respond to thrombin. We conclude that the thrombin receptor plays an unexpected role in embryonic development, suggesting a possible new function for the 'coagulation' proteases themselves. Moreover, a second platelet thrombin receptor exists, and different thrombin receptors have tissue-specific roles. This may allow development of therapeutics that will selectively block thrombin's different cellular actions.