title: [Functional roles of constitutively active calcineurin in delayed neuronal death after brain ischemia].
abstract: 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.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D019703:Calcineurin / Q000378:metabolism* / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051379:Mice; D016202:N-Methylaspartate / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000473:pathology*; D011485:Protein Binding; D015854:Up-Regulation
chemical_list: D015220:Calcium Channels; D053222:Fas Ligand Protein; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D050778:NFATC Transcription Factors; D016202:N-Methylaspartate; D019703:Calcineurin; D002154:Calpain; D002118:Calcium