Ionotropic glutamate receptor subtypes activate c-fos transcription by distinct calcium-requiring intracellular signaling pathways.
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 A2 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.
Lerea
L S
LS
Department of Medicine, Veterans Administration Medical Center, Durham, North Carolina.
McNamara
J O
JO
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016762:Genes, fos / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017470:Receptors, Glutamate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects
D002147:Calmodulin; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D012333:RNA, Messenger; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C031938:calmidazolium; D016202:N-Methylaspartate; D011494:Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; D007608:Kainic Acid; D002118:Calcium