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

doi:10.1074/jbc.M512430200

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Papers In Press, published online ahead of print April 18, 2006
J. Biol. Chem, 10.1074/jbc.M512430200
Submitted on November 21, 2005
Revised on January 17, 2006
Accepted on April 18, 2006

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

Yue Luo and Donald B. DeFranco

Pharmacology Dept., University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

Corresponding Author: dod1{at}pitt.edu

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

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