[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: Norifumi Shioda, Kohji Fukunaga
• Journal: Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan (Yakugaku Zasshi) Vol. 131 Issue 1 Pg. 13-20 (Jan 2011) ISSN: 0031-6903 [Print] Japan
• PMID: 21212608 (Publication Type: Journal Article, Review)

Chemical References

• Calcium Channels
• Fas Ligand Protein
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• NFATC Transcription Factors
• N-Methylaspartate
• Calcineurin
• Calpain
• Calcium

Topics

• Active Transport, Cell Nucleus
• Animals
• Brain Ischemia (pathology)
• Calcineurin (metabolism, physiology)
• Calcium (metabolism)
• Calcium Channels (metabolism)
• Calpain (metabolism)
• Cell Death
• Cell Nucleus (metabolism)
• Disease Models, Animal
• Fas Ligand Protein
• Forkhead Box Protein O1
• Forkhead Transcription Factors (metabolism)
• Mice
• N-Methylaspartate (metabolism)
• NFATC Transcription Factors (metabolism)
• Neurons (cytology, pathology)
• Protein Binding
• Up-Regulation