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Generation of constitutively active calcineurin by calpain contributes to delayed neuronal death following mouse brain ischemia
Author(s) -
Shioda Norifumi,
Moriguchi Shigeki,
Shirasaki Yasufumi,
Fukunaga Kohji
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03874.x
Subject(s) - nfat , calpain , calcineurin , microbiology and biotechnology , dephosphorylation , hippocampal formation , cysteine protease , biology , chemistry , phosphorylation , biochemistry , phosphatase , neuroscience , medicine , protease , enzyme , transplantation
Calpain, a Ca 2+ ‐dependent cysteine protease, in vitro converts calcineurin (CaN) to constitutively active forms of 45 kDa and 48 kDa by cleaving the autoinhibitory domain of the 60 kDa subunit. In a mouse middle cerebral artery occlusion (MCAO) model, calpain converted the CaN A subunit to the constitutively active form with 48 kDa in vivo . We also confirmed increased Ca 2+ /CaM‐independent CaN activity in brain extracts. The generation of constitutively active and Ca 2+ /CaM‐independent activity of CaN peaked 2 h after reperfusion in brain extracts. Increased constitutively active CaN activity was associated with dephosphorylation of dopamine‐regulated phosphoprotein‐32 in the brain. Generation of constitutively active CaN was accompanied by translocation of nuclear factor of activated T‐cells (NFAT) into nuclei of hippocampal CA1 pyramidal neurons. In addition, a novel calmodulin antagonist, DY‐9760e, blocked the generation of constitutively active CaN by calpain, thereby inhibiting NFAT nuclear translocation. Together with previous studies indicating that NFAT plays a critical role in apoptosis, we propose that calpain‐induced CaN activation in part mediates delayed neuronal death in brain ischemia.