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Query: UNIPROT:P06889 (Mol)
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Thirty and 60-min ischemic insults resulted in an increase in free fatty acid and 1,2- diacylglycerol contents of rat forebrain. No significant changes were detected in phospholipids except phosphatidylinositol 4-monophosphate and phosphatidylinositol 4,5-bisphosphate during ischemic insult. Phosphatidylinositol 4-monohosphate and phosphatidylinositol 4,5-bisphosphate contents decreased during ischemia. Although the increase in free fatty acid contents continued, 1,2-diacylglycerol did not show further increase after 30-min ischemia. These results suggest that there may be another pathway for the accumulation of free fatty acids in addition to phospholipase C coupled to di- and monoacylglycerol lipase. Free fatty acid and 1,2-diacylglycerol contents increased transiently and thereafter decreased to control levels within 90 min after postischemic recirculation. The decrease in arachidonic acid content preceded those of other FFA. Phosphatidylinositol 4-monophosphate and phosphatidylinositol 4,5-bisphosphate contents gradually increased after the initiation of recirculation in ischemic brains. Lysophosphatidylcholine decreased gradually after temporary increase during 15 and 5-min recirculations in 30 and 60-min ischemic groups. Phospholipase A, phospholipase C, and di- and monoacylglycerol lipase activities did not show significant changes during entire course of recirculation. Total activities of lysophospholipase and acylation enzymes of lysophospholipid demonstrated 1.5-and 2.2-fold increase during 30-min recirculation.
Mol Chem Neuropathol 1991 Feb
PMID:Changes in lipid metabolites and enzymes in rat brain due to ischemia and recirculation. 191 Mar 56

Ischemic rat brains were prepared by decapitation followed by incubation in an artificial cerebrospinal fluid at various times at 37 degrees C, and the levels of phospholipids, free fatty acids, and enzymes involved in their metabolism were studied. Activities of phospholipase A, phospholipase C, and di- and monoglyceride lipase, assayed with optimal concentrations of Ca2+ and lysophospholipase, did not significantly change by 60 min of ischemia, whereas acylation enzymes of lysophospholipid decreased in activity to an extent of 70% of control at 15 min after the ischemic treatment. The maximal activities were found at 8 x 10(-3)M, 1 x 10(-3) M, and 2 x 10(-2) M Ca2+ for phospholipase A, phospholipase C, and di- and monoglyceride lipases, respectively in microsomal fractions of both control and ischemic brain. Furthermore, the sensitivity of microsomal enzymes to endogenous Ca2+ was estimated in control and ischemic brain. The sensitivity of phospholipase C was found to be increased after 1 min of ischemic treatment, but those of phospholipase A and di- and monoglyceride lipase were not increased.
Mol Chem Neuropathol 1989 Apr
PMID:Activities of enzymes metabolizing phospholipids in rat cerebral ischemia. 274 39

Neuronal nuclei isolated from rabbit cerebral cortex were found to be enriched in an NEM-insensitive lysophosphatidic acid (lysoPA) phosphohydrolase activity. LysoPA is an inhibitor of the nuclear lysophosphatidylcholine (lysoPC) lysophospholipase, and by preserving lysoPC levels, lysoPA boosted the nuclear production of the acyl analogue of platelet-activating factor by promoting the acetylation of lysoPC (Baker and Chang, Mol. Cell Biochem., 1999, in press). The nuclear phosphohydrolase converts lysoPA to 1-monoacylglycerol, and thus eliminates this lysoPA inhibition of lysoPC lysophospholipase. The nuclear lysoPA phosphohydrolase specific activity was more than three times that observed for the nuclear lysoPA lysophospholipase (Baker and Chang, Biochim. Biophys. Acta 1438 (1999) 253-263) and represents a more active route for nuclear lysoPA removal. The neuronal nuclear lysoPA phosphohydrolase was inhibited at acidic pH, and also inhibited by calcium ions. The 1-monoacylglycerol product of the phosphohydrolase is rapidly degraded by neuronal monoacylglycerol lipase, an enzyme some sevenfold more active than the phosphohydrolase and sensitive to inhibition by arachidonoyl trifluoromethyl ketone (AACOCF(3)). Both acidic pH and free fatty acid inhibited the lipase. In the absence of AACOCF(3), production of fatty acid from lysoPA substrate could be largely attributed to the sequential actions of the nuclear phosphohydrolase and lipase. This facilitates fatty acid recycling back into phospholipid by lysophospholipid acylation when ATP levels are restored following periods of brain ischemia. At relatively low concentrations, sphingosine-1-phosphate, and alkylglycerophosphate were the most effective phosphohydrolase inhibitors while phosphatidic acid, alkylacetylglycerophosphate and ceramide were without effect. LysoPA is an interesting regulatory molecule that can potentially preserve lysophosphatidylcholine within the nuclear membrane for use in acetylation reactions. Thus conditions relevant to brain ischemia such as falling pH, falling ATP concentrations, rising fatty acid and intracellular calcium levels may, by slowing this metabolic path for lysoPA loss, promote the production of acyl PAF and contribute to the increased levels of the acetylated lipids noted in ischemia.
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PMID:A metabolic path for the degradation of lysophosphatidic acid, an inhibitor of lysophosphatidylcholine lysophospholipase, in neuronal nuclei of cerebral cortex. 1060 95

The endogenous ligands of cannabinoid receptors, also known as endocannabinoids, have been implicated in many physiological and pathological processes of the central nervous system. Here we show that the levels of the two major endocannabinoids, anandamide and 2-arachidonoyl-glycerol (2-AG), in four areas of the rat brain, change dramatically between the light and dark phases of the day. While anandamide levels in the nucleus accumbens, pre-frontal cortex, striatum and hippocampus were significantly higher in the dark phase, the opposite was observed with 2-AG, whose levels were significantly higher during the light phase in all four regions. We found that the activity of the fatty acid amide hydrolase, which catalyzes the metabolism of anandamide, was significantly lower during the dark phase, thus providing a possible explaination for the increase in anandamide levels. However, the activities of monoacylglycerol lipase and diacylglycerol lipase, two of the possible enzymes catalyzing the degradation and biosynthesis of 2-AG, respectively, changed significantly only in the striatum. These data suggest that the levels of the two major endocannabinoids might be under the control of endogenous factors known to undergo diurnal variations, and underscore the different roles, suggested by previous studies, of anandamide and 2-AG in neurophysiological processes.
Cell Mol Life Sci 2004 Apr
PMID:Differential diurnal variations of anandamide and 2-arachidonoyl-glycerol levels in rat brain. 1509 14

The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) is produced by neurons and other cells in a stimulus-dependent manner and undergoes rapid biological inactivation through transport into cells and catalytic hydrolysis. The enzymatic pathways responsible for 2-AG degradation are only partially understood. We have shown previously that overexpression of monoacylglycerol lipase (MGL), a cytosolic serine hydrolase that cleaves 1- and 2-monoacylglycerols to fatty acid and glycerol, reduces stimulus-dependent 2-AG accumulation in primary cultures of rat brain neurons. We report here that RNA interference-mediated silencing of MGL expression greatly enhances 2-AG accumulation in HeLa cells. After stimulation with the calcium ionophore ionomycin, 2-AG levels in MGL-silenced cells were comparable with those found in cells in which 2-AG degradation had been blocked using methyl arachidonyl fluorophosphonate, a nonselective inhibitor of 2-AG hydrolysis. The results indicate that MGL plays an important role in the degradation of endogenous 2-AG in intact HeLa cells. Furthermore, immunodepletion experiments show that MGL accounts for at least 50% of the total 2-AG-hydrolyzing activity in soluble fractions of rat brain, suggesting that this enzyme also contributes to 2-AG deactivation in the central nervous system.
Mol Pharmacol 2004 Nov
PMID:RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. 1527 52

Intra-abdominal fat accumulation is related to several diseases, especially diabetes and heart disease. Molecular mechanisms associated with this independent risk factor are not well established. Through the serial analysis of gene expression (SAGE) strategy, we have studied the transcriptomic effects of castration and dihydrotestosterone (DHT) in retroperitoneal adipose tissue of C57BL6 male mice. Approximately 50,000 SAGE tags were isolated in intact and gonadectomized mice, as well as 3 and 24 h after DHT administration. Transcripts involved in energy metabolism, such as glyceraldehyde-3-phosphate dehydrogenase, malic enzyme supernatant, fatty acid synthase, lipoprotein lipase, hormone-sensitive lipase and monoglyceride lipase, were upregulated by DHT. Transcripts involved in adipogenesis, and cell cycle and cell shape organization, such as DDX5, C/EBPalpha, cyclin I, procollagen types I, III, IV, V and VI, SPARC and matrix metalloproteinase 2, were upregulated by DHT. Cell defense, division and signaling, protein expression and many novel transcripts were regulated by castration and DHT. The present results provide global genomic evidence for a stimulation of glycolysis, fatty acids and triacylglycerol production, lipolysis and cell shape reorganization, as well as cell proliferation and differentiation, by DHT. The novel transcripts regulated by DHT may contribute to identify new mechanisms involved in the action of sex hormones and their potential role in obesity.
J Mol Endocrinol 2004 Oct
PMID:Effects of dihydrotestosterone on adipose tissue measured by serial analysis of gene expression. 1552 99

The levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) are under the negative control of leptin in the rodent hypothalamus. As leptin and endocannabinoids play opposite roles in the control of reproduction, we have investigated whether the impaired fertility typical of leptin-defective ob/ob mice is due, in part, to enhanced uterine endocannabinoid levels. We found that levels of both anandamide and 2-AG in the uterus of ob/ob mice are significantly elevated with respect to wild-type littermates, due to reduced hydrolase activity in the case of anandamide, and to reduced monoacylglycerol lipase and enhanced diacylglycerol lipase activity in the case of 2-AG. Furthermore, the process mediating endocannabinoid cellular uptake was also impaired in ob/ob mice, whereas the levels of cannabinoid and anandamide receptors were not modified. Although ineffective in wild-type mice, treatment of ob/ob mice with leptin re-established endocannabinoid levels and enzyme activities back to the values observed in wild-type littermates. Finally, treatment of ob/ob females with the CB1 receptor antagonist SR141716A did not improve their fertility, and inhibition of endocannabinoid inactivation with the endocannabinoid uptake inhibitor OMDM-1 in wild-type females did not result in impaired fertility.
Mol Hum Reprod 2005 Jan
PMID:Up-regulation of the endocannabinoid system in the uterus of leptin knockout (ob/ob) mice and implications for fertility. 1556 49

The zebrafish has served as a model organism for developmental biology. Sequencing its genome has expanded zebrafish research into physiology and drug-development testing. Several cannabinoid pharmaceuticals are in development, but expression of endocannabinoid receptors and enzymes remains unknown in this species. We conducted a bioinformatics analysis of the zebrafish genome using 17 human endocannabinoid genes as a reference set. Putative zebrafish orthologs were identified in filtered BLAST searches as reciprocal best hits. Orthology was confirmed by three in silico methods: phylogenetic testing, synteny analysis, and functional mapping. Zebrafish expressed orthologs of cannabinoid receptor 1, transient receptor potential channel vanilloid receptor 4, GPR55 receptor, fatty acid amide hydrolase 1, monoacylglycerol lipase, NAPE-selective phospholipase D, abhydrolase domain-containing protein 4, and diacylglycerol lipase alpha and beta; and paired paralogs of cannabinoid receptor 2, fatty acid amide hydrolase 2, peroxisome proliferator-activated receptor alpha, prostaglandin-endoperoxide synthase 2, and transient receptor potential cation channel subtype A1. Functional mapping suggested the orthologs of transient receptor potential vanilloid receptor 1 and peroxisome proliferator-activated receptor gamma lack specific amino acids critical for cannabinoid ligand binding. No orthologs of N-acylethanolamine acid amidase or protein tyrosine phosphatase, non-receptor type 22 were identified. In conclusion, the zebrafish genome expresses a shifted repertoire of endocannabinoid genes. In vitro analyses are warranted before using zebrafish for cannabinoid development testing.
Mol Genet Genomics 2007 May
PMID:A shifted repertoire of endocannabinoid genes in the zebrafish (Danio rerio). 1725 42

Our knowledge of the function of the cannabinoid system in the body has been aided by the availability of pharmacological agents that affect its function. This has been achieved by the design of agents that either directly interact with the receptor (agonists and antagonist/inverse agonists) and agents that indirectly modulate the receptor output by changing the levels of the endogenous cannabinoids (endocannabinoids). In this review, examples of the most commonly used receptor agonists, antagonists/inverse agonists, and indirectly acting agents (anandamide uptake inhibitors, fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors) are given, with particular focus upon their selectivity and, in the case of the directly acting compounds, efficacy. Finally, the links between the endocannabinoid and cyclooxygenase pathways are explored, in particular, with respect to agents whose primary function is to inhibit cyclooxygenase activity, but which also interact with the endocannabinoid system.
Mol Neurobiol 2007 Aug
PMID:The pharmacology of the cannabinoid system--a question of efficacy and selectivity. 1795 46

Depolarization-induced suppression of excitation (DSE) is a major form of cannabinoid-mediated short-term retrograde neuronal plasticity and is found in numerous brain regions. Autaptically cultured murine hippocampal neurons are an architecturally simple model for the study of cannabinoid signaling, including DSE. The transient nature of DSE--tens of seconds--is probably determined by the regulated hydrolysis of the endocannabinoid 2-arachidonoyl glycerol (2-AG). No less than five candidate enzymes have been considered to serve this role: fatty acid amide hydrolase (FAAH), cyclooxygenase-2 (COX-2), monoacylglycerol lipase (MGL), and alpha/beta-hydrolase domain (ABHD) 6 and 12. We previously found that FAAH and COX-2 do not have a role in determining the duration of autaptic DSE. In the current study, we found that two structurally distinct inhibitors of MGL [N-arachidonoyl maleimide and 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184)] prolong DSE in autaptic hippocampal neurons, whereas inhibition of ABHD6 by N-methyl-N-[[3-(4-pyridinyl)phenyl]methyl]-4'-(aminocarbonyl)[1,1'-biphenyl]-4-yl ester, carbamic acid (WWL70) had no effect. In addition, we developed antibodies against MGL and ABHD6 and determined their expression in autaptic cultures. MGL is chiefly expressed at presynaptic terminals, optimally positioned to break down 2-AG that has engaged presynaptic CB(1) receptors. ABHD6 is expressed in two distinct locations on autaptic islands, including a prominent localization in some dendrites. In summary, we provide strong pharmacological and anatomical evidence that MGL regulates DSE in autaptic hippocampal neurons and, taken together with other studies, emphasizes that endocannabinoid signaling is terminated in temporally diverse ways.
Mol Pharmacol 2009 Dec
PMID:Monoacylglycerol lipase limits the duration of endocannabinoid-mediated depolarization-induced suppression of excitation in autaptic hippocampal neurons. 1976 52


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