title: NMDA and non-NMDA receptor-mediated increase of c-fos mRNA in dentate gyrus neurons involves calcium influx via different routes.
abstract: We examined the effects of selective agonists of ionotropic excitatory amino acid (EAA) receptor subtypes on induction of the immediate early gene c-fos. We used in situ hybridization to measure c-fos mRNA and fura-2 imaging to measure intracellular calcium (Ca2+i) in individual dentate gyrus neurons maintained in vitro. Activation of either NMDA or non-NMDA receptor subtypes is sufficient to induce the rapid and dramatic increase of c-fos mRNA. Activation of either NMDA or non-NMDA receptors also induces a rapid and dramatic increase of Ca2+i, effects blocked by the removal or chelation of extracellular calcium (Ca2+e). c-fos mRNA induction by either receptor subtype is Ca2+ dependent, since chelation of Ca2+e with EGTA prevents c-fos mRNA induction by both NMDA and non-NMDA receptor agonists. The increase in Ca2+i induced by activating non-NMDA receptors is inhibited either by removal of extracellular sodium (Na+e) or by the voltage-sensitive calcium channel (VSCC) blocker nifedipine. By contrast, the increase of Ca2+i induced by activating NMDA receptors is not inhibited by removal of Na+e or nifedipine. Consistent with these effects on Ca2+i, nifedipine inhibits induction of c-fos mRNA by non-NMDA, but not by NMDA, receptor agonists. These findings indicate that Ca2+ serves as a second messenger coupling ionotropic EAA receptors with transcriptional activation of c-fos mRNA. The route of Ca2+ entry into dentate neurons, however, depends on the EAA receptor subtype stimulated. Non-NMDA receptor activation results in Ca2+ influx indirectly via VSCCs, whereas NMDA receptor activation results in Ca2+ influx directly through the NMDA channel itself.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicine, Veterans Administration Medical Center, Durham, North Carolina.
authors.forename: L S
authors.initials: LS
authors.lastname: Lerea
authors.forename: L S
authors.initials: LS
authors.lastname: Butler
authors.forename: J O
authors.initials: JO
authors.lastname: McNamara
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D009543:Nifedipine; D002118:Calcium