Brain monoglyceride lipase participating in endocannabinoid inactivation

By Thien P. Dinh, D. Carpenter, F. Leslie, Tamás F. Freund, I. Katona, S. Sensi, S. Kathuria, Daniele Piomelli. Proceedings of the National Academy of Sciences of the United States of America, 2002

1,380 citations recorded by the source corpus.

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.

Subfields: Cognitive Neuroscience, Pharmacology, Surgery

View Paper: https://www.semanticscholar.org/paper/17e5225a7ed9d79aa137c49527ba466a55e6f797

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cognitive Neuroscience

1. K. Mackie
2. Tamás F. Freund
3. Daniele Piomelli
4. L. Petrocellis
5. George Kunos
6. M. Bifulco
7. V. Di Marzo

In Pharmacology

1. V. Di Marzo
2. K. Mackie
3. Tamás F. Freund
4. P. Pacher
5. S. Batkai
6. George Kunos
7. I. Katona
8. B. Cravatt

In Surgery

1. V. Di Marzo
2. Tamás F. Freund
3. I. Katona
4. S. Batkai
5. P. Pacher
6. George Kunos
7. B. Cravatt
8. F. Bäckhed

Citations in the corpus

• The endocannabinoid system links gut microbiota to adipogenesis (2010, background): “…and 2-arachidonoylglycerol (2-AG) (Devane et al, 1992; Mechoulam et al, 1995) are endogenous CB1 and CB2 ligands, and the main enzymes responsible for their degradation are fatty acid amide hydrolase (FAAH) (Cravatt et al, 1996) and monacylglycerol lipase (MGL) (Dinh et al, 2002), respectively.”
• The emerging role of the endocannabinoid system in endocrine regulation and energy balance. (2006, background): “They are fatty acid amide hydrolase (FAAH) for anandamide and related compounds (96) and monoglycerol lipase for 2-AG (97), although other enzymes might be partially involved in the degradation of this last compound (98).”
• Endocannabinoid control of food intake and energy balance (2005, background): “The two major endocannabinoids are rapidly hydrolyzed by the fatty acid amide hydrolase and the monoacylglycerol lipase, respectivel”
• The Endocannabinoid System as an Emerging Target of Pharmacotherapy (2006, background): “Therefore, at this point it is difficult to predict the potential therapeutic usefulness of selective MGL inhibitors.”
• Distribution of cannabinoid receptors in the central and peripheral nervous system. (2005, background): “Similarly, thorough studies on the anatomical distribution of the endocannabinoid synthesizing enzymes, diacylglycerol lipase (Dinh et al. 2002) and the N-acyl phosphatidylethanolamine preferring”
• Neurobiological Interactions Between Stress and the Endocannabinoid System (2016, background): “…poorly defined uptake process mediated by a transporter mechanism (Fu et al, 2011; Hillard et al, 1997) and primarily degraded by distinct hydrolytic enzymes, the fatty acid amide hydrolase (FAAH; Cravatt et al, 2001) and monoacylglycerol lipase (MAGL; Dinh et al, 2002), respectively (Figure 1).”
• The endocannabinoid system and its therapeutic exploitation (2004, positive): “and recently shown to control 2-AG levels in isolated cells ( Box 1”
• Lipolysis – A highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores (2011, background): “More recently, MGL has also been implicated in the degradation of the bioactive MAG 2-arachidonoyl glycerol, which is known to be a potent endogenous agonist of cannabinoid receptors [78].”
• Endocannabinoid signaling as a synaptic circuit breaker in neurological disease (2008, background): “In addition, these two proteins and monoacylglycerol lipase (MGL”
• Effects of cannabinoids and cannabinoid‐enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes (2011, background): “An MAGL inactive on AEA has been suggested to act as a major 2-AG degrading enzyme (Dinh et al., 2002).”
• The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. (2003, background): “These observations, together with the presence of monoacylglycerol lipase in fat tissue, one of the main endocannabinoid-degrading enzymes (38, 39), strongly support adipose tissue as a novel physiologic and pharmacologic target for cannabinoid action.”