Protection against glutamate toxicity through inhibition of the p44/42 mitogen-activated protein kinase pathway in neuronally differentiated P19 cells

Citation
Er. Grant et al., Protection against glutamate toxicity through inhibition of the p44/42 mitogen-activated protein kinase pathway in neuronally differentiated P19 cells, BIOCH PHARM, 62(3), 2001, pp. 283-296
Citations number
55
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
62
Issue
3
Year of publication
2001
Pages
283 - 296
Database
ISI
SICI code
0006-2952(20010801)62:3<283:PAGTTI>2.0.ZU;2-N
Abstract
Excessive levels of the neurotransmitter glutamate trigger excitotoxic proc esses in neurons that lead to cell death. N-Methyl-D-aspartate (NMDA) recep tor over-activation is a key excitotoxic stimulus that leads to increases i n intracellular calcium and activation of downstream signaling pathways, in cluding the p44/42 mitogen-activated protein (MAP) kinase pathway. In the p resent study, we have demonstrated that 1,4-diamino-2,3-dicyano- 1,4-bis[2- aminophenylthio]butadiene (U0126), a potent and selective inhibitor of the p44/42 MAP kinase signaling pathway, prevents,glutamate-induced death in ne uronally differentiated P19 cells. In addition, we show that differentiated , but not undifferentiated, P19 cells expressed zeta1, epsilon1, and epsilo n2 subunits of the NMDA receptor. Differentiated P19 cells exhibited specif ic NMDA receptor binding and intracellular calcium responses to glutamate t hat were blocked by the selective NMDA receptor antagonist [5R, 10S]- [+]-5 -methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,1 (MK-801), but not U012 6. Glutamate treatment of differentiated P19 cells triggered a rapid and su stained induction in p42 MAP kinase phosphorylation that was blocked by U01 26. Pretreatment of differentiated P19 cells with U0126, but not other clas ses of protein kinase inhibitors, protected against glutamate-induced cell death. Post-treatment with U0126, even as late as 6 hr after glutamate appl ication, also protected against glutamate toxicity. These results suggest t hat thr p44/42 MAP kinase pathway may be a critical downstream signaling pa thway in glutamate receptor-activated toxicity, (C) 2001 Elsevier Science I nc. All rights reserved.