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Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin
Authors:Bisogno T  Melck D  De Petrocellis L  Di Marzo V
Institution:Istituto per la Chimica di Molecole di Interesse Biologico, Consiglio Nazionale delle Ricerche, Arco Felice, Napoli, Italy.
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.
Keywords:2-Arachidonoylglycerol  Phosphatidic acid hydrolysis  Phospholipase A2  Phospholipase C  Phospholipase D  Cannabinoid  Anandamide
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