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Lipidomics Gateway (27 January 2010) [doi:10.1038/lipidmaps.2010.3]

Endocannabinoids, including 2-arachidonoylglycerol (2-AG), are endogenous lipid mediators that activate the cannabinoid receptors.

Model of 2-arachidonoylglycerol. Visit 2-AG in the LIPID MAPS structure database for more molecular information.

The psychoactive component of marijuana is Δ9-tetrahydrocannabinol (THC), which activates the CB1 and CB2 receptors. The endogenous ligands of these receptors include anandamide (AEA) and 2-AG. Recently, the study of 2-AG function has been boosted by data from new approaches.

Formation: From rafts, on demand

2-AG is not stored in vesicles ready for use, but is instead synthesized from membrane phospholipid precursors on demand. The main route of 2-AG synthesis is thought to involve conversion of diacylglycerol (DG) by sn1-specific DG lipase. Lipid rafts, specialized membrane microdomains implicated in the regulation of signaling processes, contain the 2-AG biosynthetic machinery and are probably the main site of synthesis 1 .

Metabolism: Lipase structure a target

Monoglyceride lipase (MGLL) cleaves 2-AG and other monoacylglycerol species to liberate free fatty acids and glycerol, and tightly regulates the activity of 2-AG, especially in the brain. Aberrant expression of this enzyme can promote malignancy, as reported this month in Cancer: Growing on a free-fat diet, but this does not appear to involve 2-AG. However, MGLL is a target for drugs to exploit 2-AG signaling pathways, particularly now that the crystal structure has been solved 2 3 .

Signaling: Discriminating responses

The functions of endocannabinoids include modulation of processes that are notoriously regulated by cannabis, including appetite, pain and emotional state. However, distinguishing between the effects of AEA and 2-AG has not always been straightforward. Recently, Benjamin Cravatt and colleagues have developed a selective inhibitor to both MGLL and the enzyme that degrades AEA, and published data on the specific behavioral processes affected by these mediators. For example, 2-AG–MGLL alone regulates hypomotility, whereas AEA and 2-AG pathways interact to regulate other processes 4 . New mass spectrometry protocols tailored to the detection of 2-AG are also increasing understanding of its distribution and metabolism 5 . By studying 2-AG function, the beneficial effects of cannabis might one day be accessible to therapy, without any unwanted side effects.

Emma Leah

- Copyright © 2010 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission


  1. Placzeka, E.A., Okamotob, Y., Uedab, N. & Barker, E.L. Membrane microdomains and metabolic pathways that define anandamide and 2-arachidonyl glycerol biosynthesis and breakdown.

    Neuropharmacology 55, 1095-1104 (2008). doi:10.1016/j.neuropharm.2008.07.047

  2. Labar, G. et al. Crystal structure of the human monoacylglycerol lipase, a key actor in endocannabinoid signaling.

    ChemBioChem 11, 218-227 (2009). doi:10.1002/cbic.200900621

  3. Bertrand, T. et al. Structural basis for human monoglyceride lipase inhibition.

    J. Mol. Biol. (3 Dec 2009). doi:10.1016/j.jmb.2009.11.060

  4. Long, J.Z. et al. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo.

    Proc. Natl Acad. Sci. 106, 20270-20275 (2009). doi:10.1073/pnas.0909411106

  5. Zhang, M.-Y. et al. Simultaneous determination of 2-arachidonoylglycerol, 1-arachidonoylglycerol and arachidonic acid in mouse brain tissue using liquid chromatography/tandem mass spectrometry.

    J. Mass Spec. (30 Nov 2009). doi:10.1002/jms.1701

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