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Volume 17, Number 10, Issue of May 15, 1997 pp. 3445-3454
Copyright ©1997 Society for Neuroscience

Glutamate-Dependent Phosphorylation of Elongation Factor-2 and Inhibition of Protein Synthesis in Neurons

Received Dec. 23, 1996; revised Feb. 21, 1997; accepted Feb. 27, 1997.

Philippe Marin1, Kent L. Nastiuk2, Nadine Daniel1, Jean-Antoine Girault1, Andrew J. Czernik2, Jacques Glowinski1, Angus C. Nairn2, and Joël Prémont1

1 Chaire de Neuropharmacologie, Institut National de la Santé et de la Recherche Médicale U114, Collège de France, 75231 Paris Cedex 05, France, and 2 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021

Postischemic delayed neuronal death is attributed to excitotoxic activation of glutamate receptors. It is preceded by a persistent inhibition of protein synthesis, the molecular basis of which is not known. Here we have examined in cortical neurons in culture the regulation by glutamate of phosphorylation of eukaryotic elongation factor-2 (eEF-2) by eEF-2 kinase, a Ca2+/calmodulin-dependent enzyme. Using a phosphorylation state-specific antibody, we show that glutamate, which triggers a large influx of Ca2+, enhances dramatically the phosphorylation of eEF-2. On the basis of kinetic and pharmacological analysis, we demonstrate a close correlation among the increase in cytosolic Ca2+ concentration, the degree of eEF-2 phosphorylation, and the inhibition of protein synthesis. A 30 min treatment with NMDA induced a transient phosphorylation of eEF-2 and delayed neuronal death. However, pharmacological inhibition of protein translation was not neurotoxic by itself and protected neurons against the toxicity evoked by low concentrations of NMDA. Thus, phosphorylation of eEF-2 and the resulting depression of protein translation may have protective effects against excitotoxicity and open new perspectives for understanding long-term effects of glutamate.

Key words: elongation factor-2; phosphorylation; calcium; protein translation; glutamate; neuron




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