Evidence for bidirectional endocannabinoid transport across cell membranes

Chicca, Andrea; Marazzi, Janine; Nicolussi, Simon; Gertsch, Jürg (2012). Evidence for bidirectional endocannabinoid transport across cell membranes. Journal of biological chemistry, 287(41), pp. 34660-82. Bethesda, Md.: American Society for Biochemistry and Molecular Biology 10.1074/jbc.M112.373241

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Despite extensive research on the trafficking of anandamide (AEA) across cell membranes, little is known about the membrane transport of other endocannabinoids, such as 2-arachidonoylglycerol (2-AG). Previous studies have provided data both in favor and against a cell membrane carrier-mediated transport of endocannabinoids, using different methodological approaches. Because AEA and 2-AG undergo rapid and almost complete intracellular hydrolysis, we employed a combination of radioligand assays and absolute quantification of cellular and extracellular endocannabinoid levels. In human U937 leukemia cells, 100 nm AEA and 1 μm 2-AG were taken up through a fast and saturable process, reaching a plateau after 5 min. Employing differential pharmacological blockage of endocannabinoid uptake, breakdown, and interaction with intracellular binding proteins, we show that eicosanoid endocannabinoids harboring an arachidonoyl chain compete for a common membrane target that regulates their transport, whereas other N-acylethanolamines did not interfere with AEA and 2-AG uptake. By combining fatty acid amide hydrolase or monoacyl glycerol lipase inhibitors with hydrolase-inactive concentrations of the AEA transport inhibitors UCM707 (1 μm) and OMDM-2 (5 μm), a functional synergism on cellular AEA and 2-AG uptake was observed. Intriguingly, structurally unrelated AEA uptake inhibitors also blocked the cellular release of AEA and 2-AG. We show, for the first time, that UCM707 and OMDM-2 inhibit the bidirectional movement of AEA and 2-AG across cell membranes. Our findings suggest that a putative endocannabinoid cell membrane transporter controls the cellular AEA and 2-AG trafficking and metabolism.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
UniBE Contributor:	Chicca, Andrea, Marazzi, Janine, Nicolussi, Simon, Gertsch, Jürg
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:37
Last Modified:	05 Dec 2022 14:11
Publisher DOI:	10.1074/jbc.M112.373241
PubMed ID:	22879589
Web of Science ID:	000309654200068
URI:	https://boris.unibe.ch/id/eprint/15053 (FactScience: 222212)