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Imaging and functional regulation of microenvironment in subcellular organelle

Research Project

Project/Area Number 15390064
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General physiology
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) 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)
李 勝天  岡山大学, 大学院・医歯学総合研究科, 助手 (90325093)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2004: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 2003: ¥10,500,000 (Direct Cost: ¥10,500,000)
KeywordsCalcineurin / Calpain / Calpastatin / Neuronal cell death / Glutamate / Kainate / FK506 / Protein therapy
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

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (37 results)

All 2004 2003 Other

All Journal Article (30 results) Publications (7 results)

  • [Journal Article] カルシニューリン(PP2B)の恒常的活性化機構と神経細胞死制御-カルシニューリンとカルパインのクロストーク-2004

    • Author(s)
      松井秀樹, 呉 海燕, 富澤一仁
    • Journal Title

      細胞工学 Vol.23・No.5

      Pages: 533-537

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] タンパク質セラピー法2004

    • Author(s)
      松下正之, 富澤一仁, 松井秀樹
    • Journal Title

      実験医学 Vol.22・No.18

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Critical role of calpain-mediated cleavage of calcineurin in excitotox neurodegeneration.2004

    • Author(s)
      Wu, H.-Y., Tomizawa, K., Matsushita, M., Matsui, H.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 4929-4940

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] HIV-1 tat inhibits long-term potentiation and attenuates spatial learning.2004

    • Author(s)
      Li, S.-T., Matsushita, M., Tomizawa, K., Matsui, H.
    • Journal Title

      Ann.Neurol 55

      Pages: 362-371

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] A new cell-permeable peptide allows successful allogeneic islet transplantation in mice.2004

    • Author(s)
      Noguchi, H., Matsushita, M., Tomizawa, K., Matsui, H.
    • Journal Title

      Nature Med. 10

      Pages: 305-309

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Photo-acceleration of protein release from endosome in the protein transduction system.2004

    • Author(s)
      Matsushita, M., Tomizawa, K., Matsui, H.
    • Journal Title

      FEBS Lett. 572(1-3)

      Pages: 221-226

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Critical role of calpain-mediated cleavage of calcineurin in Excitotox neurodegeneration.2004

    • Author(s)
      Wu, H-Y., Tomizawa, K., Oda, Y., Matsushita, M., Matsui, H.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 4929-4940

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] HIV-1 tat inhibits long-term potentiation and attenuates spatial learning.2004

    • Author(s)
      Li, S-T., Matsushita, M., Moriwaki, A., Tomizawa, K., Matsui, H.
    • Journal Title

      Ann.Neurol. 55

      Pages: 362-371

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A new cell-permeable peptide allows successful allogeneic islet transplantation in mice.2004

    • Author(s)
      Noguchi, H., Matsushita, M., Okitsu, T., Tomizawa, K., Matsui, H.
    • Journal Title

      Nature Med. 10

      Pages: 305-309

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Photo-acceleration of protein release from endosome in the protein transduction system.2004

    • Author(s)
      Matsushita, M., Noguchi, H., Lu, Y.-F., Tomizawa, K., Matsui H.
    • Journal Title

      FEBS Lett. 572(1-3)

      Pages: 221-226

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] タンパク質セラピー法:Poly-Arginineによる非ウイルス的タンパク質細胞内導入と細胞内微小環境への局在化法2003

    • Author(s)
      松井秀樹, 富澤一仁, 松下正之
    • Journal Title

      日本薬理学雑誌 121巻・6号

      Pages: 435-439

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] オキシトシンの新しい生理機能2003

    • Author(s)
      富澤一仁, 松井秀樹
    • Journal Title

      医学のあゆみ Vol.206・(3)

      Pages: 225-226

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] アルギニンによる細胞内蛋白質輸送-創薬に向けて2003

    • Author(s)
      富澤一仁, 松下正之, 松井秀樹
    • Journal Title

      栄養-評価と治療 20・(5)

      Pages: 59-63

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Role of hippocampal CA2 region Following postischemic Hypothermia in gerbil.2003

    • Author(s)
      Yamashita, S., Tomizawa, K., Matsui, H.
    • Journal Title

      Mol.Brain Res. 111

      Pages: 8-16

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Oxytocin improves long-lasting spatial memory in motherhood hippocampus through MAP kinase cascade.2003

    • Author(s)
      Tomizawa, K., Matsushita, M., Matsui, H.
    • Journal Title

      Nature Neurosci. 6・(4)

      Pages: 384-390

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Protein Therapy : In Vivo Protein Transduction by Polyarginine(11R) PTD and Subcellular Targeting Delivery.2003

    • Author(s)
      Matsui, H., Tomizawa, K., Matsushita, M.
    • Journal Title

      Current Protein and Peptide Science 4

      Pages: 151-157

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Poly-arginine-fused calpastatin peptide, a livind cell membrane-permeable and specific inhibitor for calpain.2003

    • Author(s)
      Wu, H-Y., Tomizawa, K., Matsushita, M., Matsui, H.
    • Journal Title

      Neurosci.Res. 47

      Pages: 131-135

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Calcineurin Mediates Bladder Smooth Muscle Hypertrophy after Bladder outlet Obstruction.2003

    • Author(s)
      Nozaki, K., Tomizawa, K., Matsui, H.
    • Journal Title

      J.Urology 170

      Pages: 2077-2081

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Inhibition of excitatory neuronal cell death by cell permeable calcineurin autoinhibitory peptide.2003

    • Author(s)
      Terada, H., Matsushita, M., Tomizawa, K., Matsui, H.
    • Journal Title

      J.Neurochem. 8

      Pages: 1145-1151

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Cophosphorylation of amphiphysin Iand dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles.2003

    • Author(s)
      Tomizawa, K., Matsushita, M., Matsui, H.
    • Journal Title

      J.Cell Biol. 163

      Pages: 813-824

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of hippocampal CA2 region Following postischemic Hypothermia in gerbil.2003

    • Author(s)
      Yamashita, S., Miyamoto, O., Janjua, N., Tomizawa, K., Matsui, H.
    • Journal Title

      Mol.Brain Res. 111

      Pages: 8-16

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [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.
    • Journal Title

      Nature Neurosci. 6・(4)

      Pages: 384-390

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Protein Therapy : In Vivo Protein Transduction by Polyarginine(11R) PTD and Subcellular Targeting Delivery.2003

    • Author(s)
      Matsui, H., Tomizawa, K., Lu, Y-F., Matsushita, M.
    • Journal Title

      Current Protein and Peptide Science 4

      Pages: 151-157

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Poly-arginine-fused calpastatin peptide, a livind cell membrane-permeable and specific inhibitor for calpain.2003

    • Author(s)
      Wu, H-Y., Tomizawa, K., Matsushita, M.Lu, Y-F., Matsui, H.
    • Journal Title

      Neurosci.Res. 47

      Pages: 131-135

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Calcineurin Mediates Bladder Smooth Muscle Hypertrophy after Bladder outlet Obstruction.2003

    • Author(s)
      Nozaki, K., Tomizawa, K., Yokoyama, T., Kumon, H., Matsui H.
    • Journal Title

      J.Urology 170

      Pages: 2077-2081

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inhibition of excitatory neuronal cell death by cell permeable calcineurin autoinhibitory peptide.2003

    • Author(s)
      Terada, H., Matsushita, M., Lu, Y.-F., Tomizawa, K., Matsui, H.
    • Journal Title

      J.Neurochem 8

      Pages: 1145-1151

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cophosphorylation of amphiphysin land dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles.2003

    • Author(s)
      Tomizawa, K., Sunada, S., Lu, Y.-F., Matsushita, M., Matsui, H.
    • Journal Title

      J.Cell Biol. 163

      Pages: 813-824

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Oxytocin improves long-lasting spatial memory in motherhood hippocampus through MAP kinase cascade.2003

    • Author(s)
      Tomizawa, K., Matsushita, M.Matsui, H.
    • Journal Title

      Nature Neurosci. 6・(4)

      Pages: 384-390

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Protein Therapy : In Vivo Protein Transduction by Polyarginine(11R) PTD and Subcellular Targeting Delivery.2003

    • Author(s)
      Matsui, H., Tomizawa, K.Matsushita, M.
    • Journal Title

      Current Protein and Peptide Science 4

      Pages: 151-157

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cophosphorylation of amphiphysin land dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles.2003

    • Author(s)
      Tomizawa, K., Matsushita, M., Matsui, H.
    • Journal Title

      J.Cell Biol. 163

      Pages: 813-824

    • Related Report
      2004 Annual Research Report
  • [Publications] Tomizawa, K., Matsui, H.et al.: "Oxysitocin improves long-lasting spatial memory in motherhood hippocampus Through MAP kinase cascade."Nature Neurosci.. 6(4). 384-390 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsui, H.Tomizawa, K.et al.: "Protein Therapy : In Vivo Protein Thansduction by Polyarginine(11R) PTD and Subcellular Targeting Delivery."Current Protein and Peptide Science. 4. 151-157 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Wu, H-Y., Matsui, H.et al.: "Poly-arginine-fused calpastain peptide, a livind cell membrane-permeableand specific inhibitor for calpain."Neurosci.Res.. 47. 131-135 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nozaki, K., Matsui, H.et al.: "Calcineurin mediates bladder smooth muscle hypertrophy after bladder outlet obstruction."J.Urology. 170. 2077-2081 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Terada, H., Matsui, H.et al.: "Inhibition of excitatory neuronal cell death by cell permeable calcineurin Autoinhibitory peptide."J.Neurochem.. 87. 1145-1151 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tomizawa, K., Matsui, H.et al.: "Cophosphorylation of amphiphysin Iand dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles."J.Cell Biol.. 163. 813-824 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 松井秀樹, 富澤一仁, 松下正之: "日本薬理学会誌"日本薬理学会. 5 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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