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The Journal of Neuroscience, March 14, 2007, 27(11):2883-2889; doi:10.1523/JNEUROSCI.4830-06.2007
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Cellular/Molecular
Identification of a Novel Endocannabinoid-Hydrolyzing Enzyme Expressed by Microglial Cells
Giulio G. Muccioli,1 Cong Xu,1 Emma Odah,1 Eiron Cudaback,1 Jose Antonio Cisneros,3 Didier M. Lambert,4 María Luz López Rodríguez,3 Sandra Bajjalieh,1 andNephi Stella1,2 Departments of 1Pharmacology and 2Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195-7280, 3Departamento de Quimica Organica I, Facultad de Ciencias Quimicas, Universidad Complutense, E-28040 Madrid, Spain, and 4Drug Design and Discovery Center and Unité de Chimie Pharmaceutique et de Radiopharmacie, Université catholique de Louvain, B-1200 Brussels, Belgium
Correspondence should be addressed to Nephi Stella, Departments of Pharmacology and Psychiatry and Behavioral Sciences, Health Sciences Center, BB-1538c, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-7280. Email: nstella{at}u.washington.edu
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.
Key words: lipase; lipid; CB1 receptor; CB2 receptor; signaling; 2-arachidonoyl glycerol
Received Nov. 6, 2006; revised Jan. 26, 2007; accepted Feb. 1, 2007.
Correspondence should be addressed to Nephi Stella, Departments of Pharmacology and Psychiatry and Behavioral Sciences, Health Sciences Center, BB-1538c, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-7280. Email: nstella{at}u.washington.edu
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