| Project/Area Number |
12557116
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | OKAYAMA UNIVERSITY |
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Principal Investigator |
MATSUI Hideki OKAYAMA UNIVERSITY, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (30157234)
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| Co-Investigator(Kenkyū-buntansha) |
LI Sheng-tiara OKAYAMA UNIVERSITY, Graduate School of Medicine and Dentistry, Assistant, 大学院・医歯学総合研究科, 助手 (90325093)
TOMIZAWA Kazuhito OKAYAMA UNIVERSITY, Graduate School of Medicine and Dentistry, Lecturer, 大学院・医歯学総合研究科, 講師 (40274287)
MATSUSHITA Masayuki OKAYAMA UNIVERSITY, Graduate School of Medicine and Dentistry, Assistant, 大学院・医歯学総合研究科, 助手 (30273965)
OMOTO Takashi OKAYAMA UNIVERSITY, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (60032900)
MORIWAKI Akiyoshi OKAYAMA UNIVERSITY, Graduate School of Medicine and Dentistry, Associate Professor, 大学院・医歯学総合研究科, 助教授 (10144742)
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| Project Period (FY) |
2000 – 2002
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| Keywords | Calcineurin / Calpain / Calpastatin / Neuronal cell death / Apoptosis / Glutamate / Protein therapy |
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| Research Abstract |
Calcineurin and calpain, a Ca2+/calmodulin-dependent protein phosphatase and a Ca2+-dependent cysteine protease, respectively, mediate neuronal cell death through independent cascades. In this research, we showed that during neuroexcitotoxicity, calcineurin A (CnA) is directly cleaved by calpain in vitro and in vivo, resulting in the enzyme being converted to an active form. Mass spectrometry identified three cleavage sites in CnA, two of which were constitutively active forms. Overexpression of the cleaved CnA induced caspase activity and neuronal cell death. Calpain inhibitors and membrane-permeable calpastatin peptides not only blocked the cleavage of CnA, but also protected against excitotoxic neuronal cell death in vitro and in vivo. These results indicate that CnA is a crucial target for calpain, and the calpain-mediated activation of CnA triggers excitotoxic neurodegeneration. This study established a molecular link between calpain and calcineurin, thereby demonstrating a new mechanism for proteolytical regulation of calcineurin by calpain in response to certain pathological states.
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