Ionotropic glutamate receptor subtypes activate c- fos transcription by distinct calcium-requiring intracellular signaling pathways

Abstract

N-Methyl- d-aspartate (NMDA) or non-NMDA receptor activation is sufficient to induce transcription of the immediate early gene c- fos in a calcium-requiring manner. We sought to determine whether the calcium-dependent mechanisms inducing c- fos transcription are identical following activation of these two receptor subtypes. We used in situ hybridization and fura-2 imaging to detect c- fos mRNA and intracellular calcium in individual dentate gyrus neurons maintained in vitro. Structurally distinct inhibitors of phospholipase A 2 and cyclooxygenase abolished NMDA-but not kainic acid-induced increases of c- fos mRNA. Conversely, the calmodulin antagonist calmidazolium markedly inhibited kainic acid- but not NMDA-mediated increases of c- fos mRNA. We propose that the dissociation in the mechanisms transducing the calcium influx signals to the nucleus following NMDA and non-NMDA receptor activation is due to spatially distinct sites of calcium entry, resulting in activation of different enzymes located at distinct sites in the cell.