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ROLE OF THE THROMBIN RECEPTOR IN DEVELOPMENT AND EVIDENCE FOR A SECOND RECEPTOR

机译:凝血酶受体在第二受体的发育和证据中的作用

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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. [References: 30]
机译: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)。凝血酶(3)通过蛋白水解激活的G蛋白偶联受体是旨在阻止血栓形成,炎症和增殖的药物开发目标。在这里,我们表明,尽管凝血酶受体(tr)基因在小鼠中的破坏导致大约一半的tr(-/-)胚胎在胚胎第9-10天死亡,但有一半的存活成为了完全正常的成年小鼠,没有出血的素质。令人惊讶的是,tr(-/-)血小板对凝血酶反应强烈,而tr(-/-)成纤维细胞则失去了对凝血酶的反应能力。我们得出的结论是,凝血酶受体在胚胎发育中发挥了意想不到的作用,提示“凝血”蛋白酶本身可能具有新功能。此外,存在第二个血小板凝血酶受体,并且不同的凝血酶受体具有组织特异性作用。这可以允许开发治疗剂,该治疗剂将选择性地阻断凝血酶的不同细胞作用。 [参考:30]

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