Opposing roles for ERK1/2 in neuronal oxidative toxicity: distinct mechanisms of ERK1/2 action at early versus late phases of oxidative stress.

摘要: Glutamate-induced oxidative toxicity is mediated by glutathione depletion in the HT22 mouse hippocampal cell line. Previous results with pharmacological agents implicated extracellular signal-regulated kinases-1/2 (ERK1/2) glutamate cells and immature embryonic rat cortical neurons. In this report, we definitively establish a role for ERK1/2 using dominant negative MEK1 expression transiently transfected to block glutamate-induced death. contrast, chronic activation of ERK (i.e. brought about transfection constitutively active ERK2 chimera) not sufficient trigger death demonstrating that toxicity. Activation has distinct kinetic profile an initial peak occurring between 30 min 1 h treatment second typically emerging after 6 h. We demonstrate here phase induction because metabotropic receptor type I (mGluRI). mGluRI contributes adaptive response stress as enhanced upon inhibition mGluRI. The protective effect at early times restoration (GSH) levels are reduced intracellular cysteine pools. Thus, appears play dual roles acting part cellular during phases contributing later stages stress.