Brain monoglyceride lipase participating in endocannabinoid inactivation
0301 basic medicine
Endocannabinoid System Research
DNA, Complementary
Polyunsaturated Alkamides
Cells
Biological Psychology
Molecular Sequence Data
Wistar
Gene Expression
Arachidonic Acids
Glycerides
Substance Misuse
03 medical and health sciences
Complementary
Cannabinoid Receptor Modulators
Chlorocebus aethiops
Psychology
Animals
Humans
Amino Acid Sequence
Cells, Cultured
Neurons
0303 health sciences
Cultured
Biomedical and Clinical Sciences
Cannabinoid Research
Base Sequence
Cannabinoids
Hydrolysis
Neurosciences
Brain
Pharmacology and Pharmaceutical Sciences
DNA
Biological Sciences
Monoacylglycerol Lipases
Rats
3. Good health
Hela Cells
Neurological
COS Cells
Drug Abuse (NIDA only)
Endocannabinoids
HeLa Cells
DOI:
10.1073/pnas.152334899
Publication Date:
2002-09-30T16:42:53Z
AUTHORS (8)
ABSTRACT
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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