Rapid attenuation of AP-1 transcriptional factors associated with nitric oxide (NO)-mediated neuronal cell death.
Stimulation of glutamate receptors causes several intracellular reactions including activation of activator protein-1 (AP-1) production and nitric oxide (NO) generation. Exposing mouse cerebellar granule cells to N-methyl-D-aspartate or kainate (KA) in culture induced an increase of AP-1 DNA binding activity that was blocked by further addition of sodium nitroprusside (SNP), a typical NO donor. Immunoblotting using anti-c-Fos antiserum revealed the specific attenuation of AP-1, although total protein synthesis was not affected. Since the level of c-fos mRNA expression stimulated by KA remained constant even after exposure to SNP, the AP-1 attenuation can be post-transcriptionally induced. SNP did not affect the Ca2+ influx into the cells stimulated by KA. The involvement of NO in the AP-1 attenuation was supported by the fact that potassium ferrocyanide (K4Fe(CN)6), an analogue of SNP but devoid of NO, failed to inhibit the AP-1 DNA binding activity stimulated by KA. SNP alone induced neuronal cell death, which was blocked by the simultaneous addition of antioxidants, superoxide dismutase and catalase, and an NO scavenger, suggesting a direct role of peroxynitrite in the cell death. In good agreement with these effects, the AP-1 attenuation by SNP was also blocked by antioxidants. These results indicated that post-transcriptional attenuation of AP-1 is involved in the early processes of NO-mediated neuronal cell death.
Tabuchi
A
A
Department of Microbiology, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama 700, Japan. tsuda@pheasant.pharm.okayama-u.ac.jp
Oh
E
E
Taoka
A
A
Sakurai
H
H
Tsuchiya
T
T
Tsuda
M
M
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D005295:Ferrocyanides / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D013482:Superoxide Dismutase; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D005295:Ferrocyanides; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017470:Receptors, Glutamate; D018808:Transcription Factor AP-1; D009599:Nitroprusside; D009569:Nitric Oxide; D016202:N-Methylaspartate; D002374:Catalase; D013482:Superoxide Dismutase; C031835:potassium ferrocyanide; D013755:Tetradecanoylphorbol Acetate; D007608:Kainic Acid; D002118:Calcium