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Excessive Ca(2+) elevation resulting from activation of NMDA and other Ca(2+) channels is thought to play a pivotal role in pathologic events following brain ischemia. The Ca(2+) elevation directly triggers necrotic or apoptotic cell death through activation of Ca(2+)/calmodulin (CaM)-dependent enzymes, including calcineurin (CaN). CaN, a Ca(2+)/CaM-dependent serine/threonine protein phosphatase, partly mediates apoptosis associated with neuronal death. In a mouse middle cerebral artery occlusion (MCAO) model, calpain, a Ca(2+)-dependent cysteine protease, converted CaN to the constitutively active form of 48 kDa in vivo. The calpain-induced CaN activation mediated delayed neuronal death through translocation of nuclear factor of activated T-cells (NFAT) and FKHR, a forkhead box class O family member (FOXO) into neuronal nuclei after brain ischemia. The FKHR activation occurred through decreased Akt activity with concomitant dephosphorylation by constitutively active CaN. Thereafter, FKHR formed a complex with CaN and in turn translocated into nuclei after brain ischemia. After nuclear translocation of NFAT and FKHR, the transcription factors stimulated expression of Fas-ligand by binding to its promoter regions. Taken together, constitutively active CaN mediates delayed neuronal death through Fas-ligand expression via up regulation of both NFAT and FKHR transcriptional activity in brain ischemia.

The Functional Roles of Constitutively Active Calcineurin in Delayed Neuronal Death after Brain Ischemia