| Project/Area Number |
05454567
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
OHIZUMI Yasushi Tohoku University, Department of Pharmaceutical Sciences, Professer, 薬学部, 教授 (00006355)
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| Co-Investigator(Kenkyū-buntansha) |
YAGIMUMA Toshiko Tohoku University, Department of Pharmaceutical Sciences, Registrar's staff, 薬学部, 教務職員 (00250803)
MATSUOKA Setsu Tohoku University, Department of Pharmaceutical Sciences, Registrar's staff, 薬学部, 教務職員 (40238986)
FURUKAWA Ken-ichi Tohoku University, Department of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (20165468)
NAKAHATA Norimichi Tohoku University, Department of Pharmaceutical Sciences, Assistant professer, 薬学部, 助教授 (60045804)
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| Project Period (FY) |
1993 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥7,800,000 (Direct Cost: ¥7,800,000)
Fiscal Year 1995: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1994: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1993: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | Ca / Channel / Marine toxine / Platelet / Astrocytoma / Maitotoxin / Zooxanthellatoxin-A / Eudistomin / チャネル / トキシン / ズ-ザンテラトキシンA / ホスホリパーゼA_2 / トロンボキサンA_2 / MAPキナーゼ / メチルベッド / ズ-サンテラトキシンA / ホスホリパーゼC / 血管平滑筋 / Na / K-ATPase |
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| Research Abstract |
Maitotoxin (MTX) is a water-soluble toxin isolated from the dinoflagellate Gambierdiscus toxicus. We reported for the first time that MTX activates voltage-independent Ca^<2+> channels on the cardiac plasma membrane. MTX caused aggregation of rabbit washed platelets. The cytosolic Ca^<2+> concentration ([Ca^<2+>] i) was also increased by the presence of MTX.The MTX-induced platelet aggregation and [Ca^<2+>] i-increase were totally abolished in a Ca^<2+>-free solution. These results suggest that the MTX-induced platelet activation is caused by an enhanced Ca^<2+>-influx presumably through voltage-independent Ca^<2+> channels.
Zooxanthellatoxin-A (ZT-A) was isolated from a symbiotic marine alga, and the structure of ZT-A was determined to be a 62-membered lactone. ZT-A caused aggregation in rabbit platlets, but did not cause platelet aggregation or infcrease [Ca^<2+>] i in a Ca^<2+>-free solution. Indomethacin and SQ-29548 inhibited platelet aggregation and the increase in [Ca^<2+>] i ind
… More
uced by ZT-A.These results suggest that ZT-A elicited Ca^<2+>-influx from platelet plasma membranes. The resulting increase in [Ca^<2+>] i subsequently stimulates the secondary release of TXA_2 from platelets.
In platlets ZT-A caused concentration-dependent protein tyrosine phosphorylation of 42kDa in the presence of 1mM Ca^<2+>. The protein tyrosine phosphorylation was inhibited by genistein. The 42kDa protein was identified as p42^<mapk> by immunoprecipitation with an anti-mitogen-activated protein kinase (MAPK) antibody. ZT-A released thromboxame (TX) B_2 and stimulated the liberation of arachidonic acid. ZT-A-induced TXB_2 release was completely inhibited by indomethacin, while the MARK activation was partially inhibited by it. These results suggest that ZT-A may activate a protein tyrosine kinase in the presence of external Ca^<2+>. The activated protein tyrosin kinase subsequently activates MAPK.The activation of MAPK in turn causes the liberation of arachidonic acid via phospholipase A_2, resulting in the release of TXA_2 from platelets. The detailed pharmacological studies suggest that the phospolipase A_2 activation is relevant to a protein tyrosine kinase. Less
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