Glutamate Receptor Signaling Interplay Modulates Stress-sensitive Mitogen-activated Protein Kinases and Neuronal Cell Death

Pranab K Mukherjee,Mark A Decoster,Foster Z Campbell,Roger J Davis,Nicolas G Bazan

doi:10.1074/jbc.274.10.6493

Abstract

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.

Highlights

Glutamate receptors participate in neural development, plasticity, learning, memory, and pathology, Overactivation of the glutamate ionotropic receptors leads to excitotoxic cell death
The bioactive phospholipid, platelet-activating factor (PAF), is a candidate mediator of excitatory amino acid signaling because it is a retrograde messenger of long-term potentiation (LTP) [3, 4] that enhances glutamate release [5], is generated by NMDA receptor activation [6], and participates in memory formation [7,8,9]
PAF is synthetized through several pathways [10]

Summary

Introduction

Glutamate receptors participate in neural development, plasticity, learning, memory, and pathology, (e.g. excitotoxicity and neurodegenerative diseases.) Overactivation of the glutamate ionotropic receptors leads to excitotoxic cell death. Activation of the metabotropic glutamate receptor (mGluR) blocks this NMDA-signaling through PAF and MAP kinases, and the resultant 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.

Results

Conclusion