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Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin.

Abstract
In mouse neuroblastoma N18TG2 cells prelabeled with [3H]arachidonic acid ([3H]AA) the biosynthesis of 2-arachidonoylglycerol (2-AG) is induced by ionomycin in a fashion sensitive to an inhibitor of diacylglycerol (DAG) lipase, RHC 80267, but not to four different phospholipase C (PLC) blockers. Pulse experiments with [3H]AA showed that ionomycin stimulation leads to the sequential formation of [3H]phosphatidic acid ([3H]PA), [3H]DAG, and [3H]2-AG. [3H]2-AG biosynthesis in N18TG2 cells prelabeled with [3H]AA was counteracted by propranolol and N-ethylmaleimide, two inhibitors of the Mg2+/Ca2(+)-dependent brain PA phosphohydrolase. Pretreatment of cells with exogenous phospholipase D (PLD) led to a strong potentiation of ionomycin-induced [3H]2-AG formation. These data indicate that DAG precursors for 2-AG in intact N18TG2 cells are obtained from the hydrolysis of PA and not through the activation of PLC. The presence of 2% ethanol during ionomycin stimulation failed to elicit the synthesis of [3H]phosphatidylethanol and did not counteract the formation of [3H]PA, thus arguing against the activation of PLD by the Ca2+ ionophore. Selective inhibitors of secretory phospholipase A2 and the acyl-CoA acylase inhibitor thimerosal significantly reduced [3H]2-AG biosynthesis. The implications of these latter findings, and of the PA-dependent pathways of 2-AG formation described here, are discussed.
AuthorsT Bisogno, D Melck, L De Petrocellis, V Di Marzo
JournalJournal of neurochemistry (J Neurochem) Vol. 72 Issue 5 Pg. 2113-9 (May 1999) ISSN: 0022-3042 [Print] England
PMID10217292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Cyclohexanones
  • Diglycerides
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • Ionophores
  • Phosphatidic Acids
  • Prodrugs
  • Protease Inhibitors
  • Ionomycin
  • 1,6-bis(cyclohexyloximinocarbonyl)hexane
  • glyceryl 2-arachidonate
  • Lipoprotein Lipase
  • Phosphoric Monoester Hydrolases
  • Type C Phospholipases
  • Phospholipase D
Topics
  • Animals
  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Cyclohexanones (pharmacology)
  • Diglycerides (antagonists & inhibitors, metabolism)
  • Endocannabinoids
  • Enzyme Inhibitors (pharmacology)
  • Glycerides (antagonists & inhibitors, biosynthesis)
  • Hydrolysis
  • Ionomycin (pharmacology)
  • Ionophores (pharmacology)
  • Lipoprotein Lipase (antagonists & inhibitors)
  • Mice
  • Neuroblastoma (metabolism, pathology)
  • Phosphatidic Acids (metabolism)
  • Phospholipase D (pharmacology)
  • Phosphoric Monoester Hydrolases (antagonists & inhibitors)
  • Prodrugs (metabolism)
  • Protease Inhibitors (pharmacology)
  • Tumor Cells, Cultured (drug effects, metabolism)
  • Type C Phospholipases (antagonists & inhibitors)

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