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Regulation of platelet function-Pathogentical analysis of platelet signal transduction disorders

血小板功能的调节-血小板信号转导障碍的病理分析

基本信息

批准号：
17590984
负责人：
FUSE Ichiro
金额：
$ 2.24万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590984/
关键词：
thromboxane receptor ADP receptor collagen receptor phospholipase C platelet signal transdauction phospholipase C BAFF

项目摘要

We analyzed the defective site of platelet signal transduction pathway in patients with congenital platelet disorders. Six cases with impaired response to thromboxane A_2, 3 cases with impaired response to Ca ionophore A23187, and one case with impaired response to collagen were investigated.(1)Impaired platelet response to thromboxane A_2We found that Arg^<60> to Leu mutation in the first cytoplasmic loop of the thromboxane A_2 receptor (TXR) were observed in all cases with this platelet disorders. We also clarified that this mutation causes impaired coupling between TXR and phospholipase C activation, suggesting that Arg^<60> or the surrounding region in the first cytoplasmic loop of the TXR has an important role in coupling between TXR and phospholipase C.(2)Impaired response to Ca ionophore A23187The analysis of second messenger formation showed that inositol 1,4,5-triphosphate formation or Ca^<2+> mobilization induced by thrombin, STA_2 or A23187 was normal. Furthermore, the phosphorylation of 47 kDa protein (pleckstrin) and 20 kDa protein (myosin licht chain, MLC) in response to those agonists was normal. These findings suggest that the defective site in the patients' platelets lies in the process distal to or independent of protein kinase C activation, Ca^<2+> mobilization and MLC phosphorylation.(3)Impaired response to collagenThe analysis of second messenger formation showed that inositol 1,4,5-triphosphate formation or Ca^<2+> mobilization induced by thrombin, STA_2 or A23187 was normal. However, these responses to collagen were selectively defective in the patient's platelets. Furthermore, the phosphorylation of 47 kDa protein (pleckstrin) and 20 kDa protein (myosin licht chain, MLC) in response to those agonists was normal. These findings suggest that the defective site in the patients' platelets lies in the process between collagen receptor (GPVI or GPIa/IIa) and phospolipase C activation.

我们分析了先天性血小板疾病患者血小板信号转导通路的缺陷部位。本文对6例血栓素A_2、3例钙离子载体A_23187、1例胶原蛋白反应受损的患者进行了观察：(1)血栓素A_2受体(TXR)第一胞浆环对亮氨酸突变导致的血小板反应受损。我们还阐明了该突变导致TXR与磷脂酶C激活之间的偶联受损，提示该突变或TXR第一胞质环的周围区域在TXR与磷脂酶C之间的偶联中起重要作用。(2)对钙离子载体A23187的反应受损。对第二信使形成的分析表明，凝血酶、STA_2或A23187诱导的肌醇1，4，5-三磷酸的形成或钙离子的动员是正常的。此外，47 kDa蛋白(Pleckstrin)和20 kDa蛋白(myosin licht chain，MLC)对这些激动剂的反应也是正常的。这些发现表明，患者血小板中的缺陷部位位于蛋白激酶C激活、Ca~(2+)动员和MLC磷酸化的远端或独立的过程中。(3)对胶原的反应受损。第二信使形成分析表明，凝血酶、STA_2或A23187诱导的肌醇1，4，5-三磷酸形成或Ca~(2+)动员是正常的。然而，这些对胶原蛋白的反应在患者的血小板中是选择性缺陷的。此外，47 kDa蛋白(Pleckstrin)和20 kDa蛋白(myosin licht chain，MLC)对这些激动剂的反应也是正常的。这些发现表明，患者血小板中的缺陷部位存在于胶原受体(GPVI或GPIa/IIa)和磷脂酶C激活之间。