Ca2+-mediated activation of c-Jun N-terminal kinase and nuclear factor kappa B by NMDA in cortical cell cultures.
We examined the possibility that c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NF-kappaB) might be involved in intracellular signaling cascades that mediate NMDA-initiated neuronal events. Exposure of cortical neurons to 100 microM NMDA induced activation of JNK within 1 min. Activity of JNK was further increased over the next 5 min and then declined by 30 min. Similarly, ionomycin, a selective Ca2+ ionophore, induced activation of JNK. The NMDA-induced activation of JNK was abrogated in the absence of extracellular Ca2+, suggesting that Ca2+ entry is necessary and sufficient for the JNK activation. Immunohistochemistry with anti-NF-kappaB antibody demonstrated nuclear translocation of NF-kappaB within 5 min following NMDA treatment. NMDA treatment also enhanced the DNA binding activity of nuclear NF-kappaB in a Ca2+-dependent manner. Treatment with 3 mM aspirin blocked the NMDA-induced activation of JNK and NF-kappaB. Neuronal death following a brief exposure to 100 microM NMDA was Ca2+ dependent and attenuated by addition of aspirin or sodium salicylate. The present study suggests that Ca2+ influx is required for NMDA-induced activation of JNK and NF-kappaB as well as NMDA neurotoxicity. This study also implies that aspirin may exert its neuroprotective action against NMDA through blocking the NMDA-induced activation of NF-kappaB and JNK.
Ko
H W
HW
Department of Pharmacology, School of Medicine, Ajou University, Suwon, Kyungkido, Korea.
Park
K Y
KY
Kim
H
H
Han
P L
PL
Kim
Y U
YU
Gwag
B J
BJ
Choi
E J
EJ
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005333:Fetus; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016328:NF-kappa B; D016202:N-Methylaspartate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D001241:Aspirin; D002118:Calcium