title: NMDA receptor overactivation inhibits phospholipid synthesis by decreasing choline-ethanolamine phosphotransferase activity.
abstract: 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.
authors.affiliation: Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gasull
authors.forename: Elisabet
authors.initials: E
authors.lastname: Sarri
authors.forename: Nuria
authors.initials: N
authors.lastname: DeGregorio-Rocasolano
authors.forename: Ramon
authors.initials: R
authors.lastname: Trullas
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000201:enzymology; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D006868:Hydrolysis; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010713:Phosphatidylcholines / Q000096:biosynthesis / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000096:biosynthesis; D010716:Phosphatidylinositols / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010743:Phospholipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010716:Phosphatidylinositols; D010743:Phospholipids; D016194:Receptors, N-Methyl-D-Aspartate; D017855:Transferases (Other Substituted Phosphate Groups); C119514:choline-ethanolaminephosphotransferase; D010741:Phospholipases A; D054467:Phospholipases A2