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

• SHIODA Norifumi

  Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University

• FUKUNAGA Kohji

  Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University

Bibliographic Information

Other Title

• 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
• ノウキョケツ ニ ヨル シンケイ サイボウシ ニ オケル コウジョウテキ カッセイガタ カルシニューリン ノ キノウテキ ヤクワリ

Abstract

  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.<br>

Journal

• YAKUGAKU ZASSHI

  YAKUGAKU ZASSHI 131 (1), 13-20, 2011-01-01

  The Pharmaceutical Society of Japan

Keywords

• calcineurin
• calpain
• brain ischemia
• Fas-ligand

Details

• CRID: 1390001206127635072
• NII Article ID: 130000451520
• NII Book ID: AN00284903
• DOI: 10.1248/yakushi.131.13
• ISSN: 13475231
• ISSN: 00316903
• NDL BIB ID: 10957975
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I10957975
• Web Site: https://www.jstage.jst.go.jp/article/yakushi/131/1/131_1_13/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2011206704
• Text Lang: ja
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
• Abstract License Flag: Disallowed