Brain monoglyceride lipase participating in endocannabinoid inactivation
Thien P. Dinh,D. Carpenter,Frances M. Leslie,Tamás F. Freund,István Katona,Stefano L. Sensi,Satish Kathuria,Daniele Piomelli +7 more
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The results suggest that hydrolysis by means of MGL is a primary mechanism for 2-AG inactivation in intact neurons, and not on the accumulation of anandamide, another endocannabinoid lipid.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 CB1 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.read more
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Modulation of anxiety through blockade of anandamide hydrolysis
TL;DR: In this paper, Fatty acid amide hydrolase inhibitors of the Formula (I) are provided, wherein X is NH, CH2, O, or S, Q is O or S; Z is O/N; R is an aromatic moiety selected from the group consisting of substituted or unsubstituted aryl; substituted or unweighted biphenylyl, substituted or naphthyl, and substituted or unsaturated phenyl.
References
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Book
Molecular Cloning: A Laboratory Manual
TL;DR: Molecular Cloning has served as the foundation of technical expertise in labs worldwide for 30 years as mentioned in this paper and has been so popular, or so influential, that no other manual has been more widely used and influential.
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Isolation and structure of a brain constituent that binds to the cannabinoid receptor
William A. Devane,Lumir Hanus,Aviva Breuer,Roger G. Pertwee,Lesley A. Stevenson,Graeme Griffin,Dan Gibson,Asher Mandelbaum,A. Etinger,Raphael Mechoulam +9 more
TL;DR: In this article, an arachidonylethanthanolamide (anandamide) was identified in a screen for endogenous ligands for the cannabinoid receptor and its structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and confirmed by synthesis.
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Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors.
Raphael Mechoulam,Shimon Ben-Shabat,Lumir Hanus,Moshe Ligumsky,Norbert E. Kaminski,Anthony R. Schatz,Asher Gopher,Shlomo Almog,Billy R. Martin,David R. Compton,Roger G. Pertwee,Graeme Griffin,Michael Bayewitch,Jacob Barg,Zvi Vogel +14 more
TL;DR: Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature.
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2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain
Takayuki Sugiura,Sachiko Kondo,Akihiro Sukagawa,Shinji Nakane,A. Shinoda,K. Itoh,Atsushi Yamashita,Keizo Waku +7 more
TL;DR: 2-Arachidonoylglycerol was shown to bind appreciably to the cannabinoid receptor in competitive inhibition experiments and may be an endogenous cannabinoid receptor ligand in the brain.