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Does the hydrolysis of 2-arachidonoylglycerol regulate its cellular uptake?
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience. Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience. Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
2008 (English)In: Pharmacol Res, ISSN 1043-6618, Vol. 58, no 1, 72-6 p.Article in journal (Other academic) Published
Abstract [en]

Very little is known about the processes regulating the cellular uptake of the endogenous cannabinoid 2-arachidonoylglycerol (2-AG). In the present study, we investigated whether inhibition of 2-AG hydrolysis reduced its uptake, i.e. whether this compound behaves in a manner analogous to the related endocannabinoid anandamide. The selective fatty acid amide hydrolase inhibitor URB597 (3'-(aminocarbamoyl)[1,1'-biphenyl]-3-yl)-cyclohexylcarbamate) completely blocked the hydrolysis of anandamide and reduced its uptake by about half in RBL2H3 basophilic leukaemia cells. In contrast, in these cells, in PC3 and R3327AT-1 prostate cancer cells and in Neuro-2a neuroblastoma cells, the compound had more modest effects upon the hydrolysis of 2-AG and did not affect its cellular uptake at all, indicating that in these cells fatty acid amide hydrolase does not regulate the uptake of 2-AG. The serine hydrolase inhibitor methylarachidonoyl fluoronophosphonate behaved like URB597 with respect to anandamide uptake by RBL2H3 and Neuro-2a cells, and inhibited the hydrolysis of 2-AG with IC(50) values of 0.014, 0.052, 0.41 and approximately 1muM for RBL2H3, PC3, AT-1 and Neuro-2a cells, respectively. MAFP (1muM) did not significantly reduce the uptake of 2-AG by RBL2H3, PC3 and AT-1 cells but did reduce the uptake of this endocannabinoid by Neuro-2a cells. Arachidonoyl trifluoromethyl ketone and URB602 ([1,1'-biphenyl]-3-yl-carbamic acid, cyclohexyl ester) reduced the uptake of 2-AG by both RBL2H3 and Neuro-2a cells, but at the high concentrations needed, the compound also blocked the retention of these ligands by wells. It is concluded that unlike the situation for anandamide, hydrolysis of 2-AG does not regulate its cellular uptake in RBL2H3, AT-1 and PC3 cells, but may gate the uptake in Neuro-2a cells

Place, publisher, year, edition, pages
2008. Vol. 58, no 1, 72-6 p.
Identifiers
URN: urn:nbn:se:umu:diva-10515PubMedID: 18675915OAI: oai:DiVA.org:umu-10515DiVA: diva2:150186
Available from: 2008-09-23 Created: 2008-09-23 Last updated: 2009-08-07Bibliographically approved

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