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 physiological 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 hippocampal 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 cell death. The finding that the NMDA receptor-PAF-MAP kinase signaling pathway is attenuated by mGluR activation highlights the exquisite interplay between glutamate receptors in the decision making process between neuronal survival and death.
LSU Neuroscience Center, Louisiana State University Medical Center School of Medicine, New Orleans, Louisiana 70112, USA.
P K
PK
Mukherjee
M A
MA
DeCoster
F Z
FZ
Campbell
R J
RJ
Davis
N G
NG
Bazan
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016923:Cell Death; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010741:Phospholipases A / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000187:drug effects; D058924:Thienopyridines; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D058924:Thienopyridines; D014230:Triazoles; C066686:BN 50730; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase