Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat.
Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet the mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress-activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active, phosphorylation-dependent specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, has been examined following systemic administration of kainic acid (KA) at convulsant doses to rats. Increased phosphorylated MAPK (MAPK(P)) immunoreactivity has been found at 3 and 6 h in the vulnerable regions entorhinal cortex and CA3, in which neurons are committed to die, as well as in sensitive regions dentate gyrus and gyrus cinguli, in which neurons will survive. JNK(P) has been observed in the entorhinal cortex and dentate gyrus, and p38(P) immunoreactivity occurs in the entorhinal cortex. Strong c-Myc(P) expression parallels MAPK(P) immunoreactivity in the entorhinal cortex, CA3, dentate gyrus and gyrus cinguli, showing that enhanced c-Myc(P) expression does not preclude cell death or cell survival. Selective decrease of CREB(P) immunoreactivity in entorhinal cortex and CA3 indicates CREB(P) reduction associated with cell death. Strong c-Jun(P) immunoreactivity has been found in the entorhinal cortex, CA3 and dentate gyrus, thus suggesting that regulation of two opposing cellular programs (cell death or cell survival) of c-Jun(P) depends on c-Jun interactions with other factors. Interestingly, ATF-2(P), and to a lesser extent Elk-1(P), is selectively increased in the dentate gyrus. These results suggest ATF-2(P) involvement in cell survival of dentate gyrus granule cells. The present results demonstrate activation of specific MAPK pathways in association with either cell death or cell survival triggered by KA. Furthermore, increased Ras activation, as seen with p21 Ras activation assay, indicates a crucial role for Ras in activating MAP kinases following excitotoxic insult.
Ferrer
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I
Departament de Biologia Cel.lular i Anatomia Patològica, Hospital Princeps d'Espanya, Universitat de Barcelona, Campus de Bellvitge, Hospitalet de Llobregat, Spain. iferrer@sakma.es
Blanco
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R
Carmona
M
M
Puig
B
B
Domínguez
I
I
Viñals
F
F
D051698:Activating Transcription Factor 2; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C494114:Elk1 protein, rat; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D007608:Kainic Acid