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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cannabinoids have a long history of consumption for recreational and medical reasons. The primary active constituent of the hemp plant Cannabis sativa is delta9-tetrahydrocannabinol (delta9-THC). In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The toxicity of marijuana has been underestimated for a long time, since recent findings revealed delta9-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus. The acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors. The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum and striatum. The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marijuana. The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase. The discovery of endogenous cannabinoid receptor ligands, anandamide (N-arachidonylethanolamine) and 2-arachidonylglycerol made the notion of a central cannabinoid neuromodulatory system plausible. Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-dependent cleavage from a phospholipid precursor in neuronal membranes. The release of anandamide is followed by rapid uptake into the plasma and hydrolysis by fatty-acid amidohydrolase. The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marijuana. Thus, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimbic dopamine system.
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PMID:The effects of cannabinoids on the brain. 1036 32

Hydra (Cnidaria) is the first animal organism to have developed a neural network, which has been proposed to control, inter alia, the "feeding response", i.e. a mechanism through which the coelenterate opens and then closes its mouth in the presence of prey and/or glutathione. Here, we report that Hydra contains: (i) selective cannabinoid binding sites; (ii) the endogenous cannabinoid receptor ligand, anandamide (arachidonoylethanolamide); (iii) a fatty acid amide hydrolase-like activity catalysing anandamide hydrolysis; and (iv) the putative biosynthetic precursor of anandamide, N-arachidonoylphosphatidylethanolamine. We suggest that this "endogenous cannabinoid system" is involved in the modulation of the "feeding response". Anandamide (1 nM-1 microM) potently inhibited (up to 45%) the glutathione-induced "feeding response" by accelerating Hydra vulgaris mouth closure. The effect was maximal at 100 nM anandamide and was reversed by the selective antagonist of the CB1 subtype of mammalian cannabinoid receptors, SR 141716A (50-100 nM). Specific cannabinoid binding sites were detected in membranes from Hydra polyps by using [3H]SR 141716A (Kd= 1.87 nM, Bmax = 26.7 fmol/mg protein), and increasing anandamide concentrations were found to displace the binding of [3H]SR 141716A to these membranes (Ki = .505 nM). Hydra polyps were also found to contain amounts of anandamide (15.6 pmol/g) and N-arachidonoylphosphatidylethanolamine (32.4 pmol/g), as well as the other "endocannabinoid" 2-arachidonoylglycerol (11.2 nmol/g), comparable to those described previously for mammalian brain. Finally, a fatty acid amide hydrolase activity (Vmax = 3.4 nmol/min/mg protein), with subcellular distribution, pH dependency and sensitivity to inhibitors similar to those reported for the mammalian enzyme, but with a lower affinity for anandamide (Km = 400 microM), was also detected in Hydra polyps. These data suggest that the endocannabinoid signalling system plays a physiological role in Hydra that is to control the feeding response. Hydra is the simplest living organism described so far to use this recently discovered regulatory system.
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PMID:Finding of the endocannabinoid signalling system in Hydra, a very primitive organism: possible role in the feeding response. 1039 59

Identification of arachidonylethanolamide (anandamide) as an endogenous cannabinoid is one of the most important developments in cannabinoid research in recent years. In a relatively short period of time thereafter, pharmacological and biochemical studies have confirmed initial speculations that anandamide is a neuromodulator and significantly advanced our understanding of cannabinoid biochemistry. Moreover, the discovery of anandamide has led to the identification of two heretofore unknown proteins associated with cannabinoid physiology: 1) Anandamide Amidohydrolase (AAH), an enzyme responsible for the hydrolytic breakdown of anandamide and 2) the Anandamide Transporter (ANT), a carrier protein involved in the transport of anandamide across the cell membrane. Evidence obtained so far suggests that these two proteins, in combination, are responsible for the termination of the biological actions of anandamide. Also, the discovery of anandamide has revealed a novel class of more selective cannabimimetic agents possessing a somewhat different pharmacological profile of potential therapeutic value. A number of such analogs have now been reported many of which possess markedly improved cannabinoid receptor affinity and metabolic stability compared to those of the parent ligand. Generally, anandamide and all known analogs exhibit significant selectivity for the CB1 receptor and modest to very low affinity for CB2. For this reason, this group of compounds can be considered as CB1 ligands. The purpose of this review is to summarize the structure-activity relationships (SAR) of anandamide for the CB1 cannabinoid receptor and to define the structural requirements for the substrates and the inhibitors of anandamide amidohydrolase and the anandamide transporter.
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PMID:Structure-activity relationships of anandamide, an endogenous cannabinoid ligand. 1046 61

The present review summarizes the recent work carried out by our group on the link between signal transduction pathways and metabolic regulation systems as affected by cannabinoids. In cells such as astrocytes and lymphocytes, which express cannabinoid receptors, physiologically relevant doses of cannabinoids induce a remarkable metabolic stimulation as determined e.g. by enhanced glucose utilization. Studies performed in astrocytes show that the cannabinoid-evoked stimulation of glucose metabolism is independent of adenylyl cyclase inhibition, and seems to rely on the cascade CB1 cannabinoid receptor --> Sphingomyelin breakdown --> Ceramide --> Raf-1 --> Mitogen-activated protein kinase (MAPK) --> Glucose utilization. A role for phosphoinositide 3'-kinase in the stimulation of glucose utilization by cannabinoids is also put forward. In addition, ceramide generated upon CB1 cannabinoid receptor activation may enhance ketone body production by astrocytes independently of MAPK. Anandamide has also been shown to exert metabolic effects in hepatocytes, cells that do not express cannabinoid receptors. The biological role of cannabinoids as modulators of metabolism is as yet unclear.
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PMID:Effects of cannabinoids on energy metabolism. 1046 66

We have examined the possible existence of cannabinoid receptors in the isolated rat tracheal ring segments by studying the effects of some cannabinoid receptor ligands on electrically-induced contractions. Anandamide (10(-8)-3 x 10(-5)m), an endogenous ligand for cannabinoid receptors, and WIN 55,212-2 (10(-9)-3 x 10(-5)m), a moderately selective CB(2)agonist, inhibited electrically evoked contractions of the rat tracheal ring segments in a concentration-related manner. Addition of phentolamine (10(-6)m) to Krebs Henseleit solution to block alpha(2)-adrenoceptors did not affect anandamide-induced inhibition of the electrically evoked contractions. The EC(25)(-log m) values were 5.25+/-0.2 and 5.8+/-0. 4 for anandamide and WIN 55,212-2, respectively. The maximal inhibition produced by the highest concentration of the agonists used was 51.4+/-5.8% for anandamide and 35.1+/-19.5% for WIN 55, 212-2. WIN 55,212-3 also produced a concentration-dependent inhibition of the electrically evoked contractions. The maximal inhibition produced by WIN 55,212-3 was 15.8+/-2.4. The inhibitory effects of anandamide and WIN 55,212-2 were not attenuated by SR141716A (10(-6)m), a selective CB(1)receptor antagonist. Anandamide (10(-8)-3 x 10(-5)m) did not relax rat tracheal ring segments pre-contracted with carbachol (10(-6)m). These results suggest that anandamide and WIN 55,212-2 produce pre-junctional inhibitory effects in the rat trachea and that these effects were likely mediated through cannabinoid CB(2)receptors. These effects were probably non-cannabinoid receptor-mediated considering the high concentrations of the agents required to produce inhibitory responses and the effectiveness of WIN 55,212-3.
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PMID:Inhibitory effects of cannabinoid receptor ligands on electrically-evoked responses in rat isolated tracheal ring segments. 1052 56

Anandamide is an endogenous cannabinoid receptor agonist with similar pharmacological effects as D9-tetrahydrocannabinol, the major psychoactive compound in marijuana. Because anandamide does inhibit long-term potentiation, and cannabinoid abuse is known to affect learning and memory, the effects of anandamide on recombinant AMPA glutamate receptor (GluR) subunit currents were studied in Xenopus oocytes. All subunit currents were not affected by SR-1 41716A (a selective CB1 cannabinoid receptor antagonist), but were blocked by the selective AMPA antagonist CNQX and were sensitive to anandamide. Anandamide directly inhibited kainate (KA) activated homomeric GluR1; GluR3 and heteromeric GluR1/3; GluR2/3 receptor currents with IC50 values of 161+/-19, 143+/-12, 148+/-10 and 241+/-107 microM, respectively. The sensitivity of all the subunits to anandamide was not significantly different. Anandamide inhibition was voltage-independent, specific, and could not be duplicated by arachidonic acid or WIN 55,212-2 mesylate. Furthermore, anandamide effects were potentiated by forskolin (an adenylyl cyclase stimulator) and 8-bromo-cAMP (a cAMP analog), whereas MDL-HCl (an adenylyl cyclase inhibitor) caused a reversal of anandamide inhibition of GluR receptor current. Anandamide inhibition appears to be mediated by cAMP synthesis, and may underlie the involvement of this brain cannabinoid agonist in the modulation of fast synaptic transmission in the CNS.
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PMID:Anandamide inhibition of recombinant AMPA receptor subunits in Xenopus oocytes is increased by forskolin and 8-bromo-cyclic AMP. 1054 24

The electrically-evoked release of [3H]acetylcholine from hippocampal brain slices is inhibited by cannabinoid receptor agonists. The effect of palmitylsulphonyl fluoride (AM 374), a recently developed inhibitor of fatty acid amide hydrolase, in influencing the potency of exogenously added anandamide in this preparation was examined. Anandamide alone had relatively little effect on [3H]acetylcholine release. By contrast, in the presence of AM 374 (0.1 microM), anandamide produced a significant inhibition of [3H]acetylcholine release at all concentrations tested (0.1-10 microM). In addition to experiments with AM 374 the effects of N-(4-hydroxyphenyl)arachidonamide (AM 404), a putative anandamide uptake inhibitor, was also examined. However, AM 404 at concentrations up to 10 microM, was not found to significantly enhance the effect of anandamide on electrically-evoked [3H]acetylcholine release. These results indicate that AM 374 potently inhibits endogenous amidase activity and thus facilitates access of exogenous anandamide to cannabinoid receptors in the hippocampal tissue.
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PMID:Potentiation of the action of anandamide on hippocampal slices by the fatty acid amide hydrolase inhibitor, palmitylsulphonyl fluoride (AM 374). 1055 75

Anandamide and 2-arachidonoylglycerol (2-AG), two endogenous ligands of the CB1 and CB2 cannabinoid receptor subtypes, inhibit the proliferation of PRL-responsive human breast cancer cells (HBCCs) through down-regulation of the long form of the PRL receptor (PRLr). Here we report that 1) anandamide and 2-AG inhibit the nerve growth factor (NGF)-induced proliferation of HBCCs through suppression of the levels of NGF Trk receptors; 2) inhibition of PRLr levels results in inhibition of the proliferation of other PRL-responsive cells, the prostate cancer DU-145 cell line; and 3) CB1-like cannabinoid receptors are expressed in HBCCs and DU-145 cells and mediate the inhibition of cell proliferation and Trk/PRLr expression. Beta-NGF-induced HBCC proliferation was potently inhibited (IC50 = 50-600 nM) by the synthetic cannabinoid HU-210, 2-AG, anandamide, and its metabolically stable analogs, but not by the anandamide congener, palmitoylethanolamide, or the selective agonist of CB2 cannabinoid receptors, BML-190. The effect of anandamide was blocked by the CB1 receptor antagonist, SR141716A, but not by the CB2 receptor antagonist, SR144528. Anandamide and HU-210 exerted a strong inhibition of the levels of NGF Trk receptors as detected by Western immunoblotting; this effect was reversed by SR141716A. When induced by exogenous PRL, the proliferation of prostate DU-145 cells was potently inhibited (IC50 = 100-300 nM) by anandamide, 2-AG, and HU-210. Anandamide also down-regulated the levels of PRLr in DU-145 cells. SR141716A attenuated these two effects of anandamide. HBCCs and DU-145 cells were shown to contain 1) transcripts for CB1 and, to a lesser extent, CB2 cannabinoid receptors, 2) specific binding sites for [3H]SR141716A that could be displaced by anandamide, and 3) a CB1 receptor-immunoreactive protein. These findings suggest that endogenous cannabinoids and CB1 receptor agonists are potential negative effectors of PRL- and NGF-induced biological responses, at least in some cancer cells.
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PMID:Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. 1061 30

Anandamide (N-arachidonylethanolamide) is an endogenous cannabinoid that mimics the pharmacologic effects of Delta(9)-tetrahydrocannabinol, the major bioactive substance in marijuana. Anandamide appears to be synthesized, released, and inactivated by mechanisms similar to those for other neurotransmitters. Of interest to the present studies are reports that anandamide undergoes carrier-mediated uptake into neuronal or glial cells after release, followed by rapid intracellular degradation by the intracellular fatty acid amidohydrolase. In addition to effects in the brain, anandamide has multiple effects in the periphery, particularly on cells of the immune system that express both a peripheral cannabinoid receptor and amidohydrolase enzyme. We have performed a detailed characterization of anandamide uptake in the cognate mast cell line RBL-2H3 to test the hypothesis that the uptake system in peripheral cells is also carrier-mediated and functionally similar to that observed in the central nervous system. RBL-2H3 cells exhibited robust, saturable transport of [(3)H]anandamide that was both time- and temperature-sensitive. This transport activity was not dependent on extracellular ion gradients for uptake and was inhibited selectively by other fatty acid-derived molecules, anandamide congeners, and the psychoactive cannabinoids such as Delta(9)-tetrahydrocannabinol. We conclude that anandamide transport in the RBL-2H3 cells is carrier-mediated, and uptake in peripheral cells is functionally and pharmacologically identical with that observed in neurons and astrocytes.
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PMID:Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells. 1068 10

Loss of memory and cholinergic transmission are associated with both Alzheimer's disease (AD) and marijuana use. The human brain muscarinic acetylcholine receptor (mAChR), which is involved in memory function and is inhibited by arachidonic acid, is also inhibited by anandamides. Two agonists of the cannabinoid receptor derived from arachidonic acid, anandamide (AEA) and R-methanandamide, inhibit ligand binding to the mAChR. Binding of the mAChR antagonist [3H]quinuclidinyl benzilate ([3H]QNB) is inhibited up to 89% by AEA (half-maximal inhibition at 50 microM). Binding of the more polar antagonist [N-methyl-3H]scopolamine ([3H]NMS) is inhibited by AEA up to 76% (half-maximal inhibition at 44 microM). R-methanandamide inhibits more than 90% of both [3H]QNB binding (I50 = 34 microM) and [3H]NMS binding (I50 = 15 microM) to the mAChR. Both AEA and R-methanandamide stimulate mAChR binding of the agonist [3H]oxotremorine-M at low concentrations (25-75 microM), but significantly inhibit agonist binding at higher concentrations (I50 = 150 microM). The cannabinoid antagonist SR141716A did not alter AEA or R-methanandamide inhibition of [3H]NMS binding to the mAChR, even at concentrations as high as 1 microM. Further, the cannabinoid agonist WIN 55212-2 does not alter antagonist binding to the mAChR. This demonstrates that mAChR inhibition by the anandamides is not mediated by the cannabinoid receptor. Since AEA and R-methanandamide are structurally similar to arachidonic acid, they may interact with the mAChR in a similar manner to inhibit receptor function.
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PMID:Anandamides inhibit binding to the muscarinic acetylcholine receptor. 1069 Dec 92


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