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The Journal of Neuroscience, May 15, 2003, 23(10):4100-4107

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NMDA Receptor Overactivation Inhibits Phospholipid Synthesis by Decreasing Choline–Ethanolamine Phosphotransferase Activity

Teresa Gasull, Elisabet Sarri, Nuria DeGregorio-Rocasolano, and Ramon Trullas

Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain

Overactivation of NMDA receptors is believed to induce neuronal death by increasing phospholipid hydrolysis and subsequent degradation. We showed previously that NMDA releases choline and inhibits incorporation of [³H]choline into phosphatidylcholine before excitotoxic neuronal death. On the basis of these results, we hypothesized that excitotoxicity results from inhibition of synthesis rather than from increased degradation of phospholipids. We now investigated the effect of NMDA receptor overactivation on synthesis and degradation of major membrane phospholipids in the early stages of the excitotoxic process. Exposure of cortical neurons to neurotoxic concentrations of NMDA increased extracellular choline and activated hydrolysis of phosphatidylcholine and phosphatidylinositol by phospholipase A₂ but did not induce significant degradation of phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, or phosphatidylserine. In contrast, NMDA strongly reduced the incorporation of [³H]choline and [³H]ethanolamine into their respective phospholipids. Metabolic labeling experiments in whole cells showed that NMDA receptor overactivation does not modify the activity of phosphocholine or phosphoethanolamine cytidylyltransferases but strongly inhibits choline–ethanolamine phosphotransferase activity. This effect was observed well before any significant membrane damage and cell death. Moreover, cholinephosphotransferase activity was lower in microsomes from NMDA-treated cells. These results show that membrane damage by NMDA is preceded by inhibition of phospholipid synthesis and not by phospholipid degradation in the early stages of the excitotoxic process, and that NMDA receptor overactivation decreases phosphatidylcholine and phosphatidylethanolamine synthesis by inhibiting choline–ethanolaminophosphotransferase activity.

Key words: excitotoxicity; phospholipid synthesis; NMDA; choline; neuronal death; choline–ethanolamine phosphotransferase activity

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Received Dec. 16, 2002; revised Feb. 24, 2003; accepted Feb. 25, 2003.

This article has been cited by other articles:

				J. Ponce, N. P. de la Ossa, O. Hurtado, M. Millan, J. F. Arenillas, A. Davalos, and T. Gasull Simvastatin Reduces the Association of NMDA Receptors to Lipid Rafts: A Cholesterol-Mediated Effect in Neuroprotection Stroke, April 1, 2008; 39(4): 1269 - 1275. [Abstract] [Full Text] [PDF]

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