脳虚血による神経細胞死における恒常的活性型カルシニューリンの機能的役割

抄録

  Excessive Ca²⁺ elevation resulting from activation of NMDA and other Ca²⁺ channels is thought to play a pivotal role in pathologic events following brain ischemia. The Ca²⁺ elevation directly triggers necrotic or apoptotic cell death through activation of Ca²⁺/calmodulin (CaM)-dependent enzymes, including calcineurin (CaN). CaN, a Ca²⁺/CaM-dependent serine/threonine protein phosphatase, partly mediates apoptosis associated with neuronal death. In a mouse middle cerebral artery occlusion (MCAO) model, calpain, a Ca²⁺-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.