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.
Mukherjee
P K
PK
LSU Neuroscience Center, Louisiana State University Medical Center School of Medicine, New Orleans, Louisiana 70112, USA.
DeCoster
M A
MA
Campbell
F Z
FZ
Davis
R J
RJ
Bazan
N G
NG
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