Brain monoglyceride lipase participating in endocannabinoid inactivation

Proceedings of the National Academy of Sciences of the United States of America - Tập 99 Số 16 - Trang 10819-10824 - 2002
T. P. Dinh1, D. L. Carpenter1, Frances M. Leslie1, Tamás F. Freund1, István Katona1, Stefano L. Sensi1, S. P. Kathuria1, Daniele Piomelli1
1Departments of Pharmacology and Neurology, University of California, Irvine, CA 92697-4625; Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest 1450, Hungary; and Department of Neurology, University G. d'Annunzio, Chieti 66013, Italy

Tóm tắt

The endogenous cannabinoids (endocannabinoids) are lipid molecules that may mediate retrograde signaling at central synapses and other forms of short-range neuronal communication. The monoglyceride 2-arachidonoylglycerol (2-AG) meets several criteria of an endocannabinoid substance: ( i ) it activates cannabinoid receptors; ( ii ) it is produced by neurons in an activity-dependent manner; and ( iii ) it is rapidly eliminated. 2-AG inactivation is only partially understood, but it may occur by transport into cells and enzymatic hydrolysis. Here we tested the hypothesis that monoglyceride lipase (MGL), a serine hydrolase that converts monoglycerides to fatty acid and glycerol, participates in 2-AG inactivation. We cloned MGL by homology from a rat brain cDNA library. Its cDNA sequence encoded for a 303-aa protein with a calculated molecular weight of 33,367 daltons. Northern blot and in situ hybridization analyses revealed that MGL mRNA is heterogeneously expressed in the rat brain, with highest levels in regions where CB 1 cannabinoid receptors are also present (hippocampus, cortex, anterior thalamus, and cerebellum). Immunohistochemical studies in the hippocampus showed that MGL distribution has striking laminar specificity, suggesting a presynaptic localization of the enzyme. Adenovirus-mediated transfer of MGL cDNA into rat cortical neurons increased MGL expression and attenuated N -methyl-D-aspartate/carbachol-induced 2-AG accumulation in these cells. No such effect was observed on the accumulation of anandamide, another endocannabinoid lipid. The results suggest that hydrolysis by means of MGL is a primary mechanism for 2-AG inactivation in intact neurons.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 99 Số 16

10819-10824

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