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Received for publication May 4, 2004.
Revised July 21, 2004.
Accepted for publication July 22, 2004.
The endogenous cannabinoid, 2-arachidonoylglycerol (2-AG), is produced by neurons and other cells in a stimulus-dependent manner and undergoes rapid biological inactivation through transport into cells and catalytic hydrolysis. The enzymatic pathways responsible for 2-AG degradation are only partially understood. We have previously shown that overexpression of monoacylglycerol lipase (MGL), a cytosolic serine hydrolase that cleaves 1- and 2-monoacylglycerols to fatty acid and glycerol reduces stimulus-dependent 2-AG accumulation in primary cultures of rat brain neurons. We report now that RNA interference (RNAi)-mediated silencing of MGL expression greatly enhances 2-AG accumulation in HeLa cells. Following stimulation with the calcium ionophore, ionomycin, 2-AG levels in MGL-silenced cells were comparable to those found in cells in which 2-AG degradation had been blocked using methyl arachidonyl fluorophosphonate (MAFP), a non-selective inhibitor of 2-AG hydrolysis. The results indicate that MGL plays an important role in the degradation of endogenous 2-AG in intact HeLa cells. Furthermore, immunodepletion experiments show that MGL accounts for at least 50% of the total 2-AG-hydrolyzing activity in soluble fractions of rat brain, suggesting that this enzyme also contributes to 2-AG deactivation in the central nervous system.
Key words:
Cannabinoid, Mass Spectroscopy, RNA/siRNA
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