Critical Role of Calpain-mediated Cleavage of Calcineurin in Excitotoxic Neurodegeneration

Hai Yan Wu, Kazuhito Tomizawa, Yoshiya Oda, Fan Yan Wei, Yun Fei Lu, Masayuki Matsushita, Sheng Tian Li, Akiyoshi Moriwaki, Hideki Matsui

研究成果: Article

186 引用 (Scopus)

抜粋

Calcineurin and calpain, a Ca2+/calmodulin-dependent protein phosphatase and a Ca2+-dependent cysteine protease, respectively, mediate neuronal cell death through independent cascades. Here, we report 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.

元の言語English
ページ(範囲)4929-4940
ページ数12
ジャーナルJournal of Biological Chemistry
279
発行部数6
DOI
出版物ステータスPublished - 2004 2 6
外部発表Yes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • これを引用

    Wu, H. Y., Tomizawa, K., Oda, Y., Wei, F. Y., Lu, Y. F., Matsushita, M., Li, S. T., Moriwaki, A., & Matsui, H. (2004). Critical Role of Calpain-mediated Cleavage of Calcineurin in Excitotoxic Neurodegeneration. Journal of Biological Chemistry, 279(6), 4929-4940. https://doi.org/10.1074/jbc.M309767200