HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 24, 16436-16442, June 16, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/24/16436    most recent M512430200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Luo, Y. Articles by DeFranco, D. B. Search for Related Content PubMed PubMed Citation Articles by Luo, Y. Articles by DeFranco, D. B. Social Bookmarking                      What's this?

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. DeFranco¹

From the Center for Neuroscience and Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

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 min and 1 h of glutamate treatment and a second peak typically emerging after 6 h. We demonstrate here that the initial phase of ERK1/2 induction is because of 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 because of 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.

Received for publication, November 21, 2005 , and in revised form, January 17, 2006.

^* This work was supported by National Institutes of Health Grant NS38319 (to D. B. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, University of Pittsburgh School of Medicine, E1352 BST, Pittsburgh, PA 15261. Tel.: 412-624-4259; Fax: 412-648-1945; E-mail: dod1{at}pitt.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. Kumamaru, T. Numakawa, N. Adachi, Y. Yagasaki, A. Izumi, M. Niyaz, M. Kudo, and H. Kunugi Glucocorticoid Prevents Brain-Derived Neurotrophic Factor-Mediated Maturation of Synaptic Function in Developing Hippocampal Neurons through Reduction in the Activity of Mitogen-Activated Protein Kinase Mol. Endocrinol., March 1, 2008; 22(3): 546 - 558. [Abstract] [Full Text] [PDF]

				S. Khanna, S. Roy, H.-A Park, and C. K. Sen Regulation of c-Src Activity in Glutamate-induced Neurodegeneration J. Biol. Chem., August 10, 2007; 282(32): 23482 - 23490. [Abstract] [Full Text] [PDF]