N-METHYL-D-ASPARTATE RECEPTORS ACTIVATE TRANSCRIPTION OF C-FOS AND NGFI-A BY DISTINCT PHOSPHOLIPASE A(2)-REQUIRING INTRACELLULAR SIGNALING PATHWAYS

Activation of N-methyl-D-aspartate (NMDA) receptors is required for in duction of some lasting changes in nervous system structure and functi on. The cellular mechanisms involved in transducing receptor stimulati on into long-lasting changes in cellular activity are unknown. Immedia te-early genes (IEGs) have been implicated in the conversion of short term stimuli to long term changes in cellular phenotype, by regulation of gene expression. Activation of NMDA receptors on dentate gyrus neu rons triggers the transcriptional activation of several IEGs. To deter mine whether the same intracellular pathways transduce the signal from this ligand-gated ion channel to the nucleus, we compared NMDA induct ion of two IEGs. NMDA was sufficient to produce a striking increase in both c-fos and NGFI-A mRNAs in dentate granule neurons, in a calcium- dependent manner. The induction of both IEGs was blocked by structural ly distinct inhibitors of phospholipase A(2), an enzyme that catalyzes phospholipid degradation and formation of arachidonic acid. Arachidon ic acid itself is catalyzed to biologically active metabolites by mult iple enzymes, including cyclooxygenase and lipoxygenase. Selective inh ibitors of cyclooxygenase attenuated NMDA induction of c-fos but not N GFI-A. Conversely, structurally distinct inhibitors of lipoxygenase bl ocked NMDA induction of NGFI-A but not c-fos. The signaling pathways l inking NMDA receptors to the transcriptional activation of c-fos and N GFI-A are related but distinct. We suggest that phospholipase A(2) and the arachidonic acid cascade play a pivotal role in NMDA receptor reg ulation of gene expression.