2004 Fiscal Year Final Research Report Summary
Imaging and functional regulation of microenvironment in subcellular organelle
| Project/Area Number |
15390064
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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 | 一般 |
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| Research Field |
General physiology
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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) |
TOMIZAWA Kazuhito Okayama University, Graduate School of Medicine and Dentistry, Associate Professor, 大学院・医歯学総合研究科, 助教授 (40274287)
MATSUSHITA Masayuki Okayama University, Graduate School of Medicine and Dentistry, Lecture, 大学院・医歯学総合研究科, 講師 (30273965)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Calcineurin / Calpain / Calpastatin / Neuronal cell death / Glutamate / Kainate / FK506 / Protein therapy |
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| Research Abstract |
Excessive glutamate as an excitotoxic inducer plays an important role in acute and chronic neuronal cell death including ischemia, trauma, Huntington's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. Despite years of investigation, the precise mechanism involved in glutamate-induced excitotoxic neuronal cell death has not been well characterized.
Calcineurin(CaN) and calpain, a Ca^<2+>/calmodulin (CaM)-dependent protein phosphatase and a Ca^<2+>-dependent cysteine protease, respevtively, are thought to be two of the most important Ca^<2+>-dependent effectors involved in neuronal cell death. Although the mechanism of CaN-mediated neuronal cell death remains controversial, one proposed mechanism that calcineurin triggers dysfunction of the mitochondria in degenerative neurons has been strongly supported
On the other hand, calpain regulates physiological signal transduction by cleaving cytoskeletal proteins, membrane proteins and enzymes and is also thought to play a critic
… More
al role in a form of neuronal cell death involved in the pathogenesis of several diseases such as brain injury, Alzheimer's disease and focal or global cerebral ischemia. Some substrates of calpain such as p35, a specific activator of cyclin-dependent kinase 5(Cdk5) have been suggested as key molecules in the induction of neuronal cell death.
In this research, we showed that during glutamate 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 the three cleavage sites in CnA and two of them were constitutively active forms. Overexpression of the cleaved CnA induced caspase activity and neuronal cell death. Calpain inhibitors not only blocked the cleavage of calcineurin, but also protected against neuronal cell death in vitro and in vivo. These results indicate that calcineurin is a crucial target for calpain and the calpain-mediated activation of calcineurin triggers excitotoxic neurodegeneration. This further shows the direct cross talk between phosphatase and protease in pathopysiology. Less
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[Journal Article] Oxytocin improves long-lasting spatial memory in motherhood hippocampus through MAP kinase cascade.,2003
Author(s)
Tomizawa, K., Iga, N., Lu, Y-F., Matsushita, M., Matsui, H.
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Journal Title
Nature Neurosci. 6・(4)
Pages: 384-390
Description
「研究成果報告書概要(欧文)」より
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