Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies on the effects of marijuana smoking have evolved into the discovery and description of the endocannabinoid system. To date, this system is composed of two receptors, CB1 and CB2, and endogenous ligands including anandamide, 2-arachidonoyl glycerol, and others. CB1 receptors and ligands are found in the brain as well as immune and other peripheral tissues. Conversely, CB2 receptors and ligands are found primarily in the periphery, especially in immune cells. Cannabinoid receptors are G protein-coupled receptors, and they have been linked to signaling pathways and gene activities in common with this receptor family. In addition, cannabinoids have been shown to modulate a variety of immune cell functions in humans and animals and more recently, have been shown to modulate T helper cell development, chemotaxis, and tumor development. Many of these drug effects occur through cannabinoid receptor signaling mechanisms and the modulation of cytokines and other gene products. It appears the immunocannabinoid system is involved in regulating the brain-immune axis and might be exploited in future therapies for chronic diseases and immune deficiency.
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PMID:The cannabinoid system and immune modulation. 1296 Feb 89

The expression of genes encoding the cannabinoid CB(1) and CB(2) receptors and fatty acid amide hydrolase (FAAH) and the lipolytic activity of cannabinoid agonists were investigated in rat adipose tissue.RT-PCR studies indicated that the genes encoding CB(1) and CB(2) receptors and FAAH are not expressed in epididymal adipocytes. In functional studies, the non-selective cannabinoid receptor agonist WIN 55,212-2 concentration-dependently (0.01-30 micro M) induced glycerol release above baseline ( E(max) 96.1+/-6.2% of isoprenaline-induced lipolytic response). The selective CB(2) agonist JWH-015 (0.01-30 micro M) had no lipolytic activity while the endocannabinoid 2-arachidonoylglycerol and the stable anandamide derivative, R(+)-methanandamide had, only a weak lipolytic effect at the highest concentrations employed (10 and 30 micro M). The concentration/response relationship for WIN 55,212-2-mediated lipolytic activity, mimicked by the S(-)-enantiomer WIN 55,212-3, was shifted significantly to the right by the CB(1) antagonist AM 251 only at 10 micro M, but was not modified by the beta-adrenoceptor antagonist propranolol (1 micro M). The protein kinase inhibitor H-89, but not the two adenylyl cyclase inhibitors (+/-) N(6)- R-phenylisopropyladenosine (R-PIA, 1 micro M, a selective A(1) adenosine receptor agonist) or SQ 22,536 (50 micro M) significantly reduced the glycerol efflux induced by WIN 55,212-2. Our data suggest that the cannabinoid drug WIN 55,212-2 may exert lipolytic activity in male rat adipocytes via an intracellular mechanism, not activated by CB(1) or CB(2) receptor stimulation, significantly reversed by H-89 but not clearly linked to stimulation of adenylyl cyclase.
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PMID:CB1- and CB2-cannabinoid receptor-independent lipolysis induced by WIN 55,212-2 in male rat adipocytes. 1456 52

Diacylglycerol (DAG) lipase activity is required for axonal growth during development and for retrograde synaptic signaling at mature synapses. This enzyme synthesizes the endocannabinoid 2-arachidonoyl-glycerol (2-AG), and the CB1 cannabinoid receptor is also required for the above responses. We now report on the cloning and enzymatic characterization of the first specific sn-1 DAG lipases. Two closely related genes have been identified and their expression in cells correlated with 2-AG biosynthesis and release. The expression of both enzymes changes from axonal tracts in the embryo to dendritic fields in the adult, and this correlates with the developmental change in requirement for 2-AG synthesis from the pre- to the postsynaptic compartment. This switch provides a possible explanation for a fundamental change in endocannabinoid function during brain development. Identification of these enzymes may offer new therapeutic opportunities for a wide range of disorders.
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PMID:Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. 1461 53

The past decade has witnessed a rapid expansion of our understanding of the biological roles of cannabinoids and their cognate receptors. It is now certain that Delta9-tetrahydrocannabinol, the principle psychoactive component of the Cannabis sativa plant, binds and activates membrane receptors of the 7-transmembrane domain, G-protein-coupled superfamily. Several putative endocannabinoids have since been identified, including anandamide, 2-arachidonyl glycerol and noladin ether. Synthesis of numerous cannabinomimetics has also greatly expanded the repertoire of cannabinoid receptor ligands with the pharmacodynamic properties of agonists, antagonists and inverse agonists. Collectively, these ligands have proven to be powerful tools both for the molecular characterisation of cannabinoid receptors and the delineation of their intrinsic signalling pathways. Much of our understanding of the signalling mechanisms activated by cannabinoids is derived from studies of receptors expressed by tumour cells; hence, this review provides a succinct summary of the molecular pharmacology of cannabinoid receptors and their roles in tumour cell biology. Moreover, there is now a genuine expectation that the manipulation of cannabinoid receptor systems may have therapeutic potential for a diverse range of human diseases. Thus, this review also summarises the demonstrated antitumour actions of cannabinoids and indicates possible avenues for the future development of cannabinoids as antitumour agents.
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PMID:Cannabinoid receptor systems: therapeutic targets for tumour intervention. 1464 Sep 10

The effects of endogenous and synthetic cannabinoid receptor agonists, including 2-arachidonoylglycerol (2-AG), R-methanandamide, WIN55,212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], and CP 55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol], and the psychoactive constituent of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), on the function of homomeric alpha7-nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp technique. The endogenous cannabinoid receptor ligands 2-AG and the metabolically stable analog of anandamide (arachidonylethanolamide), R-methanandamide, reversibly inhibited currents evoked with ACh (100 microM) in a concentration-dependent manner (IC50 values of 168 and 183 nM, respectively). In contrast, the synthetic cannabinoid receptor agonists CP 55,940, WIN55,212-2, and the phytochemical Delta9-THC did not alter alpha7-nACh receptor function. The inhibition of alpha7-mediated currents by 2-AG was found to be non-competitive and voltage-independent. Additional experiments using endocannabinoid metabolites suggested that arachidonic acid, but not ethanolamine or glycerol, could also inhibit the alpha7-nACh receptor function. Whereas the effects of arachidonic acid were also noncompetitive and voltage-independent, its potency was much lower than 2-AG and anandamide. Results of studies with chimeric alpha7-nACh-5-hydroxytryptamine (5-HT)3 receptors comprised of the amino-terminal domain of the alpha7-nACh receptor and the transmembrane and carboxyl-terminal domains of 5-HT3 receptors indicated that the site of interaction of the endocannabinoids with the alpha7-nAChR was not located on the N-terminal region of the receptor. These data indicate that cannabinoid receptor ligands that are produced in situ potently inhibit alpha7-nACh receptor function, whereas the synthetic cannabinoid ligands, and Delta9-THC, are without effect, or are relatively ineffective at inhibiting these receptors.
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PMID:Differential effects of endogenous and synthetic cannabinoids on alpha7-nicotinic acetylcholine receptor-mediated responses in Xenopus Oocytes. 1510 30

1 The relationship of agonist efficacy to the rate of G protein-coupled receptor signaling desensitization is controversial. 2 Expressing inwardly rectifying potassium channels (GIRKs) in Xenopus oocytes, we have devised a signaling assay that clearly identifies CB1 cannabinoid receptor agonists with low intrinsic efficacy. 3 In this assay, the synthetic CB1 agonists, AM411, AM782, AM1902, AM2233 and WIN55,212-2 and the endogenous cannabinoid, 2-arachidonoyl ester, were full agonists. 4 The synthetic CB1 agonist AM356 (methanandamide), the endogenous cannabinoids, anandamide and 2-arachidonoyl ether, and the phytocannabinoid, Delta9THC, were partial agonists. 5 The rate of desensitization of CB1 was independent of agonist efficacy. WIN55,212-2, AM782, AM1902, AM2233, and 2-arachidonoyl glycerol ester all desensitized quickly, with desensitization rates varying from 14% min(-1) to 10% min(-1). AM356, AM411, anandamide, and Delta9THC all desensitized considerably slower, at a rate of 5% min(-1). 6 Despite high potency and efficacy, AM411 desensitized as slowly as anandamide and Delta9THC. 7 CB1 agonist efficacy and rate of desensitization are not necessarily related.
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PMID:Identification of a potent and highly efficacious, yet slowly desensitizing CB1 cannabinoid receptor agonist. 1514 60

Actions of endocannabinoids in the cerebellum can be demonstrated following distinct stimulation protocols in Purkinje cells. First, depolarization-induced elevations of intracellular Ca2+ lead to the suppression of neurotransmitter release from both inhibitory and excitatory afferents. In another case, postsynaptic group I metabotropic glutamate receptors (mGluRs) trigger a strong inhibition of the glutamatergic inputs from parallel and climbing fibers. Both pathways involve endocannabinoids retrogradely acting on type 1 cannabinoid receptors (CB1Rs) at presynaptic terminals. Here, we show that group I mGluR activation also depresses GABAergic transmission at the synapses between molecular layer interneurons and Purkinje cells. Using paired recordings, we found that application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine reduced the evoked IPSCs in Purkinje cells. This effect was independent of postsynaptic Ca2+ increases and was completely blocked by a CB1R antagonist. Experiments performed with the GTP-analogues GDP-betaS and GTP-gammaS provided evidence that endocannabinoids released after G-protein activation can also inhibit GABAergic inputs onto nearby, unstimulated Purkinje cells. Block of the enzymes DAG lipase or phospholipase C reduced the group I mGluR-dependent inhibition, suggesting that 2-arachidonyl glycerol could act as retrograde messenger. Finally, group I mGluR activation by brief bursts of activity of the parallel fibers induced a short-lived depression of spontaneous IPSCs via presynaptic CB1Rs. Our results reveal a mechanism with potential physiological importance, by which glutamatergic synapses induce an endocannabinoid-mediated inhibition of the GABAergic inputs onto Purkinje cells.
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PMID:Group I metabotropic glutamate receptors inhibit GABA release at interneuron-Purkinje cell synapses through endocannabinoid production. 1515 47

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) catalyse the hydrolysis of the endocannabinoids anandamide and 2-arachidonoyl glycerol. We investigated their ultrastructural distribution in brain areas where the localization and effects of cannabinoid receptor activation are known. In the hippocampus, FAAH was present in somata and dendrites of principal cells, but not in interneurons. It was located mostly on the membrane surface of intracellular organelles known to store Ca(2+) (e.g. mitochondria, smooth endoplasmic reticulum), less frequently on the somatic or dendritic plasma membrane. MGL immunoreactivity was found in axon terminals of granule cells, CA3 pyramidal cells and some interneurons. In the cerebellum, Purkinje cells and their dendrites are intensively immunoreactive for FAAH, together with a sparse axon plexus at the border of the Purkinje cell/granule cell layers. Immunostaining for MGL was complementary, the axons in the molecular layer were intensively labelled leaving the Purkinje cell dendrites blank. FAAH distribution in the amygdala was similar to that of the CB(1) cannabinoid receptor: evident signal in neuronal somata and proximal dendrites in the basolateral nucleus, and hardly any labelling in the central nucleus. MGL staining was restricted to axons in the neuropil, with similar relative signal intensities seen for FAAH in different nuclei. Thus, FAAH is primarily a postsynaptic enzyme, whereas MGL is presynaptic. FAAH is associated with membranes of cytoplasmic organelles. The differential compartmentalization of the two enzymes suggests that anandamide and 2-AG signalling may subserve functional roles that are spatially segregated at least at the stage of metabolism.
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PMID:Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. 1523 53

The effects of cannabinoid receptor ligands including 2-arachidonoylglycerol, R-methanandamide, Delta9-THC (Delta9-tetrahydrocannabinol), WIN 55,212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], CP 55,940 ([1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol]) and a series of fatty acids on depolarization-induced Ca2+ effluxes mediated by voltage-dependent Ca2+ channels were investigated comparatively in transverse tubule membrane vesicles from rabbit skeletal muscle. Vesicles were loaded with 45Ca2+ and membrane potentials were generated by establishing potassium gradients across the vesicle using the ionophore valinomycin. Endocannabinoids, 2-arachidonoylglycerol and R-methanandamide (all 10 microM), inhibited depolarization-induced Ca2+ effluxes and specific binding of [3H]PN 200-110 (isradipine) to transverse tubule membranes. On the other hand, synthetic cannabinoids, including CP 55,940, WIN 55,212-2, and Delta9-THC (all 10 microM), were ineffective. Additional experiments using endocannabinoid metabolites suggested that whereas ethanolamine and glycerol were ineffective, arachidonic acid inhibited Ca2+ effluxes and specific binding of [3H]PN 200-110. Further studies indicated that only those fatty acids containing two or more double bonds were effective in inhibiting depolarization-induced Ca2+ effluxes and specific binding of [3H]PN 200-110. These results indicate that endocannabinoids, but not synthetic cannabinoids, directly inhibit the function of voltage-dependent calcium channels (VDCCs) and modulate the specific binding of calcium channel ligands of the dihydropyridine (DHP) class.
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PMID:Differential effects of endogenous and synthetic cannabinoids on voltage-dependent calcium fluxes in rabbit T-tubule membranes: comparison with fatty acids. 1546 89

Singing by adult male zebra finches is a learned behavior important for courtship, kin recognition, and nest defense (Zann, 1996) and is inhibited by both brief periods of limited food availability and systemic injection of cannabinoids. These similar effects on singing, combined with increasing evidence for endocannabinoid involvement in feeding behavior, led us to evaluate a possible shared mechanism. We found that limited food availability both reduces singing in a cannabinoid antagonist-reversible manner and increases levels of the endocannabinoid 2-arachidonyl glycerol in various brain regions including the caudal telencephalon, an area that contains auditory telencephalon including the L2 subfield of L (L2) and caudal medial nidopallium (NCM). Development and use of an anti-zebra finch cannabinoid receptor type 1 (CB1) antibody demonstrates distinct, dense cannabinoid receptor expression within song regions including Area X, lMAN (lateral magnocellular nucleus of anterior nidopallium), HVC, RA (robust nucleus of arcopallium), and L2. NCM receives L2 projections and is implicated in integration of auditory information. Activity in this area, determined through expression of the transcription factor ZENK, is increased after exposure to unfamiliar song. Because previous work has shown that these novel song-stimulated increases in NCM activity are mitigated by cannabinoid exposure, we tested and found that similar effects on ZENK expression are produced by limiting food. Limited food-related reductions in the activity of NCM neurons were reversed by the cannabinoid antagonist SR141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide), implicating CB1 cannabinoid receptor involvement. Taken together, these experiments indicate a link between feeding state and gene expression related to auditory perception that is mediated by endocannabinoid signaling.
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PMID:Endocannabinoids link feeding state and auditory perception-related gene expression. 1552 87


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