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.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA009789, DA017259, DA026161] and the Skaggs Institute for Chemical Biology.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.069427.
Please see the related article on page 996.
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ABBREVIATIONS:
- AEA
- N-arachidonylethanolamine (anandamide)
- 2-AG
- 2-arachidonylglycerol
- FAAH
- fatty acid amide hydrolase
- MAGL
- monoacylglycerol lipase
- WIN55,212-2
- (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone
- JZL184
- 4-nitrophenyl-4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate.
- Received October 14, 2010.
- Accepted October 14, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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