| Co-Investigator(Kenkyū-buntansha) |
FURUKAWA Tatsuo Niigata University, Hospital, Associate professor, 医歯学総合病院, 助教授 (00272849)
TOBA Ken Niigata University, Hospital, Lecturer, 医歯学総合病院, 講師 (60313540)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
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_2
We 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 A23187
The 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 collagen
The 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.
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