Premium
Neuronal Protein Kinase Signaling Cascades and Excitotoxic Cell Death
Author(s) -
SKAPER STEPHEN D.,
FACCI LAURA,
STRIJBOS PAUL J.L.M.
Publication year - 2001
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2001.tb03606.x
Subject(s) - excitotoxicity , glutamate receptor , microbiology and biotechnology , neurotoxicity , ask1 , protein kinase a , map kinase kinase kinase , nmda receptor , mitogen activated protein kinase , kinase , biology , mitogen activated protein kinase kinase , neuroscience , chemistry , receptor , biochemistry , organic chemistry , toxicity
A bstract : Perturbation of normal survival mechanisms may play a role in a large number of disease processes. Glutamate neurotoxicity, particularly when mediated by the N ‐methyl‐d‐aspartate (NMDA) subtype of glutamate receptors, has been hypothesized to underlie several types of acute brain injury, including stroke. Several neurological insults linked to excessive release of glutamate and neuronal death result in tyrosine kinase activation, including p44/42 mitogen activated protein (MAP) kinase. To further explore a role for MAP kinase activation in excitotoxicity, we used a novel tissue culture model to induce neurotoxicity. Removal of the endogenous blockade by Mg 2+ of the NMDA receptor in cultured hippocampal neurons triggers a self perpetuating cycle of excitotoxicity, which has relatively slow onset, and is critically dependent on NMDA receptors and activation of voltage gated Na + channels. These injury conditions led to a rapid phosphorylation of p44/42 that was blocked by MAP kinase kinase (MEK) inhibitors. MEK inhibition was associated with protection against synaptically mediated excitotoxicity. Interestingly, hippocampal neurons preconditioned by a sublethal exposure to Mg 2+ ‐free conditions were rendered resistant to injury induced by a subsequently longer exposure to this insult; the preconditioning effect was MAP kinase dependent. The MAP kinase signaling pathway can also promote polypeptide growth factor mediated neuronal survival. MAP kinase regulated pathways may act to promote survival or death, depending upon the cellular context in which they are activated.