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

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188 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4929-4940
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number6
DOIs
Publication statusPublished - Feb 6 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    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