N-methyl-D-aspartate signaling to nuclear activator protein-1 through mechanisms different from those for kainate signaling in murine brain.

Protein de novo synthesis is mainly under the control at the level of gene transcription by transcription factors in cell nuclei in eukaryotes. The systemic administration of N-methyl-D-aspartate resulted in selective but transient potentiation of binding of a radiolabeled double-stranded oligonucleotide probe for the nuclear transcription factor activator protein-1 in murine hippocampus, without markedly affecting binding of probes for other transcription factors. By contrast, kainic acid induced more potent and more persistent potentiation of activator protein- binding in the hippocampus than N-methyl-D-aspartate. The protein synthesis inhibitor cycloheximide was effective in significantly preventing the potentiation by N-methyl-D-aspartate, but not that by kainic acid at the doses used. Moreover, kainic acid induced much more and longer expression of immunoreactive c-Fos protein in the hippocampus than N-methyl-D-aspartate. However, neither N-methyl-D-aspartate nor kainate induced expression of cyclic AMP response element binding protein phosphorylated at serine133 in the hippocampus from 10 min to 24 h after the administration. Instead, kainate was more potent than N-methyl-D-aspartate in facilitating both dephosphorylation at serine and phosphorylation at tyrosine of particular nuclear proteins in the hippocampus. These results suggest that N-methyl-D-aspartate and kainate signals may be differentially transduced into cell nuclei to express the activator protein-1 complex through molecular mechanisms which differ from phosphorylation of cyclic AMP response element binding protein at serine133 but involve serine dephosphorylation and/or tyrosine phosphorylation of particular nuclear proteins in the murine hippocampus.