Endocannabinoid overload Lichtman, Aron H; Blankman, Jacqueline L; Cravatt, Benjamin F
Molecular pharmacology
78, Issue:
6
Journal Article
Peer reviewed
Open access
The signaling capacity of endogenous cannabinoids ("endocannabinoids") is tightly regulated by degradative enzymes. This Perspective highlights a research article in this issue (p. 996) in which the ...authors show that genetic disruption of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), causes marked elevations in 2-AG levels that lead to desensitization of brain cannabinoid receptors. These findings highlight the central role that MAGL plays in endocannabinoid metabolism in vivo and reveal that excessive 2-AG signaling can lead to functional antagonism of the brain cannabinoid system.
ABSTRACT
PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts) is a recently described autosomal‐recessive neurodegenerative disease caused by mutations in the ...α−β−hydrolase domain‐containing 12 gene (ABHD12). Only five homozygous ABHD12 mutations have been reported and the pathogenesis of PHARC remains unclear. We evaluated a woman who manifested short stature as well as the typical features of PHARC. Sequence analysis of ABHD12 revealed a novel heterozygous c.1129A>T (p.Lys377*) mutation. Targeted comparative genomic hybridization detected a 59‐kb deletion that encompasses exon 1 of ABHD12 and exons 1–4 of an adjacent gene, GINS1, and includes the promoters of both genes. The heterozygous deletion was also carried by the patient's asymptomatic mother. Quantitative reverse transcription‐PCR demonstrated ∼50% decreased expression of ABHD12 RNA in lymphoblastoid cell lines from both individuals. Activity‐based protein profiling of serine hydrolases revealed absence of ABHD12 hydrolase activity in the patient and 50% reduction in her mother. This is the first report of compound heterozygosity in PHARC and the first study to describe how a mutation might affect ABHD12 expression and function. The possible involvement of haploinsufficiency for GINS1, a DNA replication complex protein, in the short stature of the patient and her mother requires further studies.
We identified two novel mutations in ABHD12 in a woman with PHARC, a heterozygous p.Lys377* mutation and a 59‐kb deletion that encompasses exon 1 of ABHD12, exons 1‐4 of GINS1, and the promoters of both genes. In this first functional study of the effect of ABHD12 mutations, we demonstrated a 50% decrease in ABHD12 RNA expression and absence of ABHD12 hydrolase activity. Haploinsufficiency for GINS may play a role in the short stature of the patient and her mother.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Endogenous ligands for cannabinoid receptors (“endocannabinoids”) include the lipid transmitters anandamide and 2-arachidonoylglycerol (2-AG). Endocannabinoids modulate a diverse set of physiological ...processes and are tightly regulated by enzymatic biosynthesis and degradation. Termination of anandamide signaling by fatty acid amide hydrolase (FAAH) is well characterized, but less is known about the inactivation of 2-AG, which can be hydrolyzed by multiple enzymes in vitro, including FAAH and monoacylglycerol lipase (MAGL). Here, we have taken a functional proteomic approach to comprehensively map 2-AG hydrolases in the mouse brain. Our data reveal that ∼85% of brain 2-AG hydrolase activity can be ascribed to MAGL, and that the remaining 15% is mostly catalyzed by two uncharacterized enzymes, ABHD6 and ABHD12. Interestingly, MAGL, ABHD6, and ABHD12 display distinct subcellular distributions, suggesting that they may control different pools of 2-AG in the nervous system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The enzyme fatty acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes ...the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB
1 receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB
1 receptor-mediated cardiovascular depression is related to increased G protein coupling of CB
1 receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH
−/− mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.
► Unique pharmacological profile of novel fatty acid amide hydrolase inhibitor ► Selectivity of AM3506 in FAAH inhibition in brain over liver in vivo ► AM3506 as centrally acting antihypertensive agent with minimal cardiovascular effects under normotensive conditions and without adverse metabolic effects
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
2-Arachidonoylglycerol (2-AG) is a lipid messenger that acts at cannabinoid receptors, the molecular targets of the psychoactive component of marijuana, Δ9-tetrahydrocannabinol (THC). 2-AG signaling ...regulates many physiological processes and is terminated by rapid enzymatic degradation. The work in this thesis describes the identification of brain enzymes that can cleave 2-AG in vitro and the biochemical, metabolomic, cellular and behavioral consequences of inactivating these enzymes in vivo. In Chapter 1, we developed a functional proteomics strategy to inventory the 2-AG hydrolases expressed in mouse brain and found that virtually all of the activity could be ascribed to three enzymes: monoacylglycerol lipase (MAGL) and the uncharacterized serine hydrolases alpha/beta hydrolases 6 and 12 (ABHD6 and ABHD12). As described in Chapter 2, genetic and pharmacological MAGL disruption in mice confirmed this enzyme's role as the principal 2-AG hydrolase in the brain and revealed significant cellular and behavioral adaptations caused by prolonged elevations in brain 2-AG. Recently, mutations in ABHD12 were found to cause the human neurodegenerative disease PHARC. In Chapter 3, we describe the generation and characterization of ABHD12–/– mice, which develop a PHARC-related phenotype at an advanced age. Global lipidomic analysis revealed that bulk brain 2-AG levels are unchanged following ABHD12 disruption and identified phosphatidylserine lipids as novel ABHD12-regulated metabolites, suggesting that dysregulation of the latter pro-apoptotic lipid class may contribute to the development of this devastating disease.
The enzyme fatty-acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes ...the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB
1
receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB
1
receptor-mediated cardiovascular depression is related to increased G-protein coupling of CB
1
receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH
−/−
mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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