Regulation of c-Jun N-terminal kinase,p38 kinase and AP-1 DNA binding in cultured brain neurons: roles in glutamate excitotoxicity and lithium neuroprotection |
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Authors: | Chen Ren-Wu Qin Zheng-Hong Ren Ming Kanai Hirohiko Chalecka-Franaszek Elzbieta Leeds Peter Chuang De-Maw |
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Institution: | Molecular Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA. |
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Abstract: | In rat cerebellar granule cells, glutamate induced rapid activation of c-Jun N-terminal kinase (JNK) and p38 kinase to phosphorylate c-Jun (at Ser63) and p53 (at Ser15), respectively, and a subsequent marked increase in activator protein-1 (AP-1) binding that preceded apoptotic death. These glutamate-induced effects and apoptosis could largely be prevented by long-term (7 days) pretreatment with 0.5-2 mm lithium, an antibipolar drug. Glutamate's actions could also be prevented by known blockers of this pathway, MK-801 (an NMDA receptor blocker), SB 203580 (a p38 kinase inhibitor) and curcumin (an AP-1 binding inhibitor). The concentration- and time-dependent suppression of glutamate's effects by lithium and curcumin correlated well with their neuroprotective effects. These results suggest a prominent role of JNK and p38, as well as their downstream AP-1 binding activation and p53 phosphorylation in mediating glutamate excitotoxicity. Moreover, the neuroprotective effects of lithium are mediated, at least in part, by suppressing NMDA receptor-mediated activation of the mitogen-activated protein kinase pathway. |
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Keywords: | AP-1 excitotoxicity JNK lithium neuroprotection p38 p53 phosphorylation |
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