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Regulation of the Arachidonic Acid Cascade and PAF Metabolism in Reproductive Tissues
Published in Murray D. Mitchell, Eicosanoids in Reproduction, 2020
John M. Johnston, Noriei Maki, Marlane J. Angle, Dennis R. Hoffman
In support of the view that diacylglycerol was produced physiologically by phospholipase C, we demonstrated that diacylglycerol was produced in increased amounts in amnion tissue obtained from women in labor and that the diacylglycerol had a fatty acid composition almost identical to that of the parent phosphatidylinositol.49 This experiment provided further support for the presence of a phosphatidylinositol-specific phospholipase C in amnion tissue. The diacylglycerol produced in this tissue can be metabolized by at least two pathways: (1) diacylglycerol lipase or (2) phosphorylation by a diacylglycerol kinase. The activity of diacylglycerol lipase in amnion tissue was shown to be highest in the microsomal fraction and specific for the ester bond at the sn-1 position, producing fatty acid and 2-monoacylglycerol.50 This diacylglycerol lipase also preferentially cleaved diacylglycerol containing arachidonoyl in the sn-2 position. Monoacylglycerol lipase activity was also demonstrated in the cytosolic fraction of amnion tissue.50 The specific activity of monoacylglycerol lipase was significantly greater than that of diacylglycerol lipase and preferentially catalyzed the hydrolysis of 2-monoacylglycerol containing an arachidonoyl group. Based on the subcellular distribution and the effects of various inhibitors, it was concluded that monoacylglycerol lipase and diacylglycerol lipase in fetal membranes and decidua tissue were two distinct enzyme activities.
Endocannabinoid Role in Gut Health *
Published in Betty Wedman-St Louis, Cannabis as Medicine, 2019
Endocannabinoids are known to regulate gut motility, the time it takes for food to move through the intestines. Slow gut motility is more commonly called constipation, and fast gut motility is known as diarrhea. Evidence indicates that the endocannabinoid system plays an important role in gut motility. In obese mice fed high-fat diets, the endocannabinoid system in the gut underwent alterations, leading to an increase in gut motility.10 Many studies also indicate that CB1 receptor activation suppresses peristalsis and gastrointestinal contraction. The CB1 receptor is activated by THC, the psychoactive component in marijuana.11,12 Because CBD does not activate the CB1 receptor, it may be less likely to produce constipation. This was indicated in a mouse model of sepsis, which demonstrated that CBD slowed gastrointestinal motility in the animals with sepsis but did not affect motility in normal mice.13 Furthermore, CBD regulates the activity of FAAH, an enzyme involved in gastrointestinal motility through its actions on anandamide.13 Additional evidence that the endocannabinoid system is involved in gut motility was provided by a mouse model of constipation in which inhibiting diacylglycerol lipase (DGL), the enzyme responsible for the synthesis of the endocannabinoid 2-AG, improves gut motility.14
Phosphoinositide Metabolism
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
Both inositol 1,4,5-trisphosphate and 1,2-diacylglycerol are generated at the membrane level by activation of the enzyme, polyphosphoinositide phosphodiesterase. Physiological levels of Ca2+ are required for an optimal activation of this Ca2+-dependent enzyme.88 The coupling factor linking surface receptors and polyphosphoinositide phosphodiesterase is a G protein.89 Inositol 1,4,5-trisphosphate and diacylglycerol may function as second messengers to activate signaling pathways that may also be responsible for the release of arachidonic acid and for the activation of guanylyl cyclase. Degradation of 1,2-diacylglycerol by the activity of diacylglycerol lipase results in production of arachidonic acid and monoacylglycerol. Arachidonic acid is a polyunsaturated fatty acid that is oxygenated to produce eicosanoids, a family of compounds that includes prostaglandins, thromboxane, and leukotrienes. Release of arachidonic acid is the principal mechanism for stimulation of eicosanoid biosynthesis, but studies using the tumor cell line Lu-65, derived from human nonsmall cell lung cancer indicate that arachidonate release and stimulation of prostaglandin synthesis can proceed via either calcium/phospholipase A,-dependent and -independent pathways.90
The function of the endocannabinoid system in the pancreatic islet and its implications on metabolic syndrome and diabetes
Published in Islets, 2023
Edgardo Cortes-Justo, Sergio H Garfias-Ramírez, Alonso Vilches-Flores
The endocannabinoid system (ECS) is a lipid signaling complex involved in metabolism regulation and specific physiological processes. Today, ECS role in the development and treatment of some diseases, including metabolic syndrome and type-2 Diabetes Mellitus, is still under research.1,2 The ECS was discovered after the use of tetrahydrocannabinol (THC) and the activation of a transmembrane G protein-coupled receptor (GPR) in the nervous system, renamed cannabinoid receptor 1 (CB1).3,4 CB2 and GPR55 receptors were discovered by their interaction with endogenous ligands identified as endocannabinoids (EC): N-arachidonyl ethanolamine, also named anandamide (AEA), and 2-arachidonylglycerol (2-AG), both derived from phospholipids containing arachidonic acid (AAc).5–7 Enzymes involved in biosynthesis and degradation of EC are present in many cells, anchored in the plasmatic membrane or close to: AEA production is regulated by N-acyl phosphatidylethanolamine phospholipase D (NAPE-D), and degradation by fatty acid-acyl hydrolase (FAAH), meanwhile 2-AG depends of diacylglycerol lipase (DAGL) for synthesis and monoacyl-glycerol lipase (MAGL) for metabolism.
Medical cannabis and cannabinoids in rheumatology: where are we now?
Published in Expert Review of Clinical Immunology, 2019
Piercarlo Sarzi-Puttini, Alberto Batticciotto, Fabiola Atzeni, Laura Bazzichi, Manuela Di Franco, Fausto Salaffi, Daniela Marotto, Angela Ceribelli, Jacob N Ablin, Winfred Hauser
Trans-Δ9-tetrahydrocannabinol (THC, the primary psychoactive constituent of cannabis) was first isolated in the 1960s [6,7], and the identification of cannabinoid receptors 1 and 2 (CBr1 and CBr2) led to the isolation and characterization of their endogenous ligands, the endocannabinoids N-arachidonoyl-ethanolamine (AEA, also known as anandamide), 2-arachidonoylglycerol (2-AG), 2-archidonoylglyceral ether (noladin ether), O-archidonoyl ethanolamine (virodhamine) and N-arachidonoyl dopamine. Five main enzymes are involved in their biosynthesis and inactivation: N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD), sn-1-specific diacylglycerol lipase-α (DGLα), DGLβ, fatty acid amide hydrolase 1 (FAAH), and monoacylglycerol lipase (MAGL, also known as MGL) [8–10].
Investigational cannabinoids in seizure disorders, what have we learned thus far?
Published in Expert Opinion on Investigational Drugs, 2018
Dejana Ružić Zečević, Marko Folić, Ziyad Tantoush, Milan Radovanović, Goran Babić, Slobodan M. Janković
Investigational cannabinoids with anticonvulsant action mostly use mechanisms which do not include CB1 and CB2 receptors. Cannabidiol in vitro antagonizes CB1 and CB2 receptor agonists, but it is believed that its anticonvulsant action is associated with at least some of the following mechanisms: stimulation of 5-HT1a receptors, inhibition of glutamate release, inhibition of noradrenaline, dopamine and adenosine reuptake, stimulation of glycine receptors, and stimulation and desensitization of transient receptor potential class channels (ankyrin and vanilloid types, i.e. TRPA1, TRPV1, and TRPV2 receptors) [14]. Anticonvulsant effect of cannabidivarin is probably related to its agonistic action on TRPA1, TRPV1, and TRPV2 receptors, similar as that of cannabidiol, while its inhibitory action on diacylglycerol lipase-α, which synthesizes 2-arachidonoylglycerol, an endocannabinoid, remains yet to be connected to anticonvulsant properties [15,16]. Δ9-tetrahydrocannabivarin is an antagonist of CB1 receptors, and partial agonist of CB2 receptors; an unconfirmed hypothesis was made that increasing GABA release by blocking CB1 receptors for endocannabinoids is the basis for Δ9-tetrahydrocannabivarin anticonvulsant action [17]. Δ9-tetrahydrocannabinolic acid has little affinity and efficacy at CB1 and CB2 receptors [18], and it activates TRPA1 and TRPV4 channels and blocks TRPM8 channels. Δ9-tetrahydrocannabinolic acid also inhibits diacylglycerol lipase alpha, but all these mechanisms of action were not unequivocally connected to anticonvulsant activity [19].