Generation of constitutively active calcineurin by calpain contributes to delayed neuronal death following mouse brain ischemia

Norifumi Shioda, Shigeki Moriguchi, Yasufumi Shirasaki, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)

Abstract

Calpain, a Ca2+-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 Ca2+/CaM-independent CaN activity in brain extracts. The generation of constitutively active and Ca2+/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.

Original languageEnglish
Pages (from-to)310-320
Number of pages11
JournalJournal of Neurochemistry
Volume98
Issue number1
DOIs
Publication statusPublished - 2006 Jul

Keywords

  • Brain ischemia
  • Calcineurin
  • Calmodulin
  • Calpain
  • NFAT
  • Neuronal death

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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