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Review
. 2010 Dec;78(6):993-5.
doi: 10.1124/mol.110.069427. Epub 2010 Oct 15.

Endocannabinoid overload

Aron H Lichtman  1 , Jacqueline L Blankman, Benjamin F Cravatt
Affiliations
Review

Endocannabinoid overload

Aron H Lichtman et al. Mol Pharmacol. 2010 Dec.

Abstract

The signaling capacity of endogenous cannabinoids ("endocannabinoids") is tightly regulated by degradative enzymes. This Perspective highlights a research article in this issue (p. 996) in which the authors show that genetic disruption of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), causes marked elevations in 2-AG levels that lead to desensitization of brain cannabinoid receptors. These findings highlight the central role that MAGL plays in endocannabinoid metabolism in vivo and reveal that excessive 2-AG signaling can lead to functional antagonism of the brain cannabinoid system.

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Figures

Fig. 1.
Fig. 1.
Model for 2-AG signaling at CB1 receptors in the nervous system. A, under normal conditions, 2-AG is synthesized postsynaptically by diacylglycerol lipase (DAGL), traverses across the synapse to activate CB1 receptors located presynaptically, and then is rapidly inactivated by MAGL. B, after long-term MAGL blockade, elevated 2-AG levels cause tonic activation and eventual internalization and down-regulation of CB1 receptors.
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