Glutamate receptor signaling interplay modulates stress-sensitive mitogen-activated protein kinases and neuronal cell death

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.