Glutamate receptors modulate multiple signaling pathways, several of which
involve mitogen-activated protein (MAP) kinases, with subsequent physiologi
cal or pathological consequences. Here we report that stimulation of the N-
methyl-D-aspartate (NMDA) receptor, using platelet-activating factor (PAF)
as a messenger, activates MAP kinases, including c-Jun NH2-terminal kinase,
p38, and extracellular signal-regulated kinase, in primary cultures of hip
pocampal neurons. Activation of the metabotropic glutamate receptor (mGluR)
blocks this NMDA-signaling through PAF and MAP kinases, and the resultant
cell death. Recombinant PAF-acetylhydrolase degrades PAF generated by NMDA
receptor activation; the hetrazepine BN50730 (an intracellular PAF receptor
antagonist) also inhibits both NMDA-stimulated MAP kinases and neuronal ce
ll death. The finding that the NMDA receptor-PAF-MAP kinase signaling pathw
ay is attenuated by mGluR activation highlights the exquisite interplay bet
ween glutamate receptors in the decision making process between neuronal su
rvival and death.