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Role of Calpain-mediated Cleavage of Calcineurin in Excitotoxic Neurodegeneration

Research Project

Project/Area Number 12557116
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Cerebral neurosurgery
Research InstitutionOKAYAMA UNIVERSITY

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)

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)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥10,200,000 (Direct Cost: ¥10,200,000)
Fiscal Year 2002: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥4,000,000 (Direct Cost: ¥4,000,000)
KeywordsCalcineurin / Calpain / Calpastatin / Neuronal cell death / Apoptosis / Glutamate / Protein therapy / カルシウムチャネル / 免疫抑制剤 / FK506結合蛋白質 / シクロスポリン / 膀胱肥大 / FK506 / 蛋白質セラピー / In vivo Protein Transduction / TAT / Aキナーゼ / 長期増強 / PKI
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.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (41 results)

All Other

All Publications (41 results)

  • [Publications] Matsushita M., Matsui H.et al.: "A high efficiency protein transduction system proving the role of PKA in long lasting LTP."J.Neurosci.. 21(16). 6000-6007 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomizawa, K., Matsui H.et al.: "Cdk5/P35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity."J.Neurosci.. 22(7). 2590-2597 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Li, S-T., Matsui H.et al.: "Calcineurin Plays Different Roles in Group II Metabotropic Glutamate Receptor- and NMDA Receptor-Dependent Long-Term Depression."J.Neurosci.. 22(12). 5034-5041 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takenobu, T., Matsui H.et al.: "Development of p53 protein transduction therapy using membrane-permeable peptides and the application to oral cancer cells."Mol.Cancer Therapeutics. 1. 1043-1049 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsui, H., Tomizawa, K.: "Protein Therapy : In Vivo Protein Transduction by Polyarginine(11R) PTD and Subcellular Targeting Delivery."Current Protein and Peptide Science. 4. 151-157 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomizawa, K., Matsui H.et al.: "Oxytocin improves long-lasting spatial memory in motherhood hippocampus through MAP kinase cascade."Nature Neurosci.. 6(4). 384-390 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wu, H-Y., Matsui, H.et al.: "Poly-arginine-fused calpastatin peptide, a livind cell membrane-permeable and specific inhibitor for calpain."Neurosci.Res.. 47. 131-135 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nozaki, K., Matsui, H.et al.: "Calcineurin Mediates Bladder Smooth Muscle Hypertrophy after Bladder outlet Obstruction."J.Urology. 170. 2077-2081 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomizawa, K., Matsui, H.et al.: "Cophosphorylation of amphiphysin land dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles."J.Cell Biol.. 163. 813-824 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wu, H-Y., Matsui, H.et al.: "Critical role of calpain-mediated cleavage of calcineurin in excitotoxic neurodegeneration."J.Biol.Chem.. 279. 4929-4940 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Li, S.-T., Matsui, H.et al.: "HIV-1 tat inhibits long-term potentiation and attenuates spatial learning."Ann.Neurol.. 55. 362-371 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Noguchi, H., Matsui, H.et al.: "A new cell-permeable peptide allows successful allogeneic islet transplantation in mice."Nature Med.. 10. 305-309 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 富澤一仁, 松下正之, 杉本直巳, 松井秀樹: "化学"遺伝子治療からタンパク質セラピーへ. 5 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsushita M., Tomizawa K., Moriwaki M., Li S-H., Terada H., Ohmoto T., Matsui H.: "A high efficiency protein transduction system proving the role of PKA in long lasting LTP."J.Neurosci.. 21(16). 6000-6007 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomizawa, K., Ohta, J., Matsushita, M., Moriwaki, A., Li, S-T., Takei, K., Matsui, H.: "Cdk5/P35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity."J.Neurosci.. 22(7). 2590-2597 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Li, S-T., Kato, K., Tomizawa, K., Matsushita, M., Moriwaki, A., Matsui, H., Mikoshiba, K.: "Calcineurin Plays Different Roles in Group II Metabotropic Glutamate Receptor-and NNIDA Receptor-Dependent Long-Term Depression."J.Neurosci.. 22(12). 5034-5041 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takenobu, T., Tomizawa, K., Matsushita, M., Li, S.-T., Moriwaki, A., Lu, Y.-F., Matsui, H.: "Development of p53 protein transduction therapy using membrane-permeable peptides and the application to oral cancer cells."Mol.Cancer Therapeutics. 1. 1043-1049 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Matsui, H., Tomizawa, K., Lu Y.-F., Matsushita, M.: "Protein Therapy : In Vivo Protein Transduction by Polyarginine(11R) PTD and Subcellular Targeting Delivery."Current Protein and Peptide Science. 4. 151-157 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomizawa, K., Iga, N., Lu, Y.-F., Moriwaki, A., Matsushita, M., Li, S.-T., Miyamoto, O., Itano, T., Matsui, H.: "Oxytocin improves long-lasting spatial memory in motherhood hippocampus through MAP kinase cascade."Nature Neurosci.. 6(4). 384-390 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wu, H-Y., Tomizawa, K., Matsushita, M., Lu, Y-F., Li, S-T., Matsui, M.: "Poly-arginine-fused calpastatin peptide, a livind cell membrane-permeable and specific inhibitor for calpain."Neurosci.Res.. 47. 131-135 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nozaki, K., Tomizawa, K., Yokoyama, T., Kumon, H., Matsui H.: "Calcineurin Mediates Bladder Smooth Muscle Hypertrophy after Bladder outlet Obstruction."J.Urology,. 170. 2077-2081 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomizawa, K., Sunada, S., Lu, Y.-F., Oda, Y., Kinuta, M., Ohshima, T., Saito, T., Wei F.-Y., Matsushita, M., Li, S.-T., Tsutsui, K., Hisanaga, S., Mikoshiba, K., Takei, K., Matsui, H.: "Cophosphorylation of amphiphysin I and dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles."J.Cell Biol.. 163. 813-824 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wu, H.-Y., Tomizawa, K., Oda, Y., Wei, F.-Y., Lu, Y.-F., Matsushita, M., Li, S.-T., Moriwaki, A., Matsui, H.: "Critical role of calpain-mediated cleavage of Calcineurin in excitotoxic neurodegeneration."J.Biol.Chem.. 279. 4929-4940 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Noguchi, H., Matsushita, M., Okitsu, T., Moriwaki, A., Tomizawa, K., Kang, S., Li, S.-T., Kobayashi, N., Matsumoto, S., Tanaka, K., Tanaka, N., Matsui, H.: "A new cell-permeable peptide allows successful allogeneic islet transplantation in mice."Nature Med.. 10. 305-309 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Li, S.-T., Matsushita, M., Moriwaki, A., Saheki, Y., Lu, Y.-F., Tomizawa, K., Wu, H.-Y., Terada, H., Matsui, H.: "HIV-1 tat inhibits long-term potentiation and attenuates spatial learning."Ann.Neurol.. 55(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomizawa, K., Ohta, J.et al.: "Cdk5/P35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity"J.Neurosci.. 22(7). 2590-2597 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Li, S-T., Kato, K.: "Calcineurin Plays Different Roles in Group II Metabotropic Glutamate Receptor-and NMDA Receptor-Dependent Long-Term Depression"J.Neurosci.. 22(12). 5034-5041 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Seki, Y., Ikeda, S.: "Sequencing analysis of a putative human O-sialoglycoprotein endopeptidase gene (OSGEP) and analysis of a bidirectional promoter between the OSGEP and APEX genes"Gene.. 285. 101-108 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takenobu, T., Tomizawa, K.: "Development of p53 protein transduction therapy using membrane-permeable peptides and the application to oral cancer cells"Mol.Cancer Therapeutics. 1. 1043-1049 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 富澤一仁, 松下正之, 杉本直己, 松井秀樹: "遺伝子治療からタンパク質セラピーへ"化学. 57巻9号. 50-55 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsushita, M., Tomizawa, K, et al.: "A high efficiency protein transduction system proving the role of PKA in long lasting LTP"J.Neurosci.. 21(16). 6000-6007 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kurazono, S., Okamoto, M, et al.: "Recombinant core protein fragment of phosphacan, a brain specific chondroitin sulfate proteoglycan, promote excitotoxic cell death of cultured rat hippocampal neurons"Neurosci.Lett.. 304(3). 169-172 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kurazono, S., Okamoto, M, et al.: "Expression of brain specific chondroitin sulfate proteoglycans, neurocan and phosphacan, in the developing and adult hippocampus of Ihara's epileptic rats"Brain Res.. 898. 36-48 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tomizawa, K., Ohata, J, et al.: "Cdk5/P^<35> regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity"J.Neurosci.. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] 松井 秀樹, 的崎 尚: "蛋白質 核酸 酵素"共立出版. 4 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyamoto,O.,Matsui,H. et al.: "Depression of long term potentiation in gerbil hippocampus following postischemic hypothermia."Brain Res.. 873(1). 168-172 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Cho,S.I.,Matsushita,M. et al.: "Novel compounds,'1,3-selenazine derivatives' as specific inhibitors of eukaryotic elongation factor 2-kinase (calmodulin-dependent protein kinase-III)"B.B.A.. 1475. 207-215 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tomizawa,K.,Matsui,H. et al.: "Involvement of Cyclin-dependent kinase 5/p35nck5a in the synaptic recorganization of rat hippocampus during kindling progression."Jpn.J.Physiol.. 50. 525-532 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Feng,J.,Tomizawa,K. et al.: "Spinophilin regulates the formation and function of dendritic spines."Proc.Natl.Acad.Sci.USA. 97. 9287-9292 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tokunaga,K.,Kusaka,N. et al.: "Coil embolization of intradural pseudoaneurysms caused by arterial injury during surgery : report of two cases."Am.J.Neuroradiol.. 22(1). 35-39 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Aoi,M.,Date,I. et al.: "Single or continuous injection of glial cell line-derived neurotrophic factor in the striatum induces recovery of the nigrostriatal dopaminergic system."Neurol.Res.. 22(8). 832-836 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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