1: J Neurosci. 2007 Mar 14;27(11):2883-9.

Identification of a novel endocannabinoid-hydrolyzing enzyme expressed by
microglial cells.

Muccioli GG, Xu C, Odah E, Cudaback E, Cisneros JA, Lambert DM, Lopez Rodriguez
ML, Bajjalieh S, Stella N.

Department of Pharmacology, University of Washington, Seattle, Washington
98195-7280, USA.

The endocannabinoids (eCBs) anandamide and 2-arachidonoyl glycerol (2-AG) are
inactivated by a two-step mechanism. First, they are carried into cells, and
then anandamide is hydrolyzed by fatty acid amide hydrolase (FAAH) and 2-AG by
monoacylglycerol lipase (MGL). Here we provide evidence for a previously
undescribed MGL activity expressed by microglial cells. We found that the mouse
microglial cell line BV-2 does not express MGL mRNA and yet efficiently
hydrolyzes 2-AG. URB597 (3'-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate) reduces
this hydrolysis by 50%, suggesting the involvement of FAAH. The remaining
activity is blocked by classic MGL inhibitors [[1,1-biphenyl]-3-yl-carbamic
acid, cyclohexyl ester (URB602) and MAFP (methylarachidonyl fluorophosphate)]
and is unaffected by inhibitors of COXs (cyclooxygenases), LOXs
(lipooxygenases), and DGLs (diacylglycerol lipases), indicating the involvement
of a novel MGL activity. Accordingly, URB602 leads to selective accumulation of
2-AG in intact BV-2 cells. Although MGL expressed in neurons is equally
distributed between the cytosolic, mitochondrial, and nuclear fractions, the
novel MGL activity expressed by BV-2 cells is enriched in mitochondrial and
nuclear fractions. A screen for novel inhibitors of eCB hydrolysis identified
several compounds that differentially block MGL, FAAH, and the novel MGL
activity. Finally, we provide evidence for expression of the novel MGL by mouse
primary microglia in culture. Our results suggest the presence of a novel,
pharmacologically distinct, MGL activity that controls 2-AG levels in microglia.

PMID: 17360910 [PubMed - in process]

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