UNIPROT:P21554 - FACTA Search

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

Data, initially anecdotal, but recently supported on more solid experimental evidence, suggest that cannabinoids might be beneficial in the treatment of some of the symptoms of multiple sclerosis (MS). Despite this evidence, there are no data on the possible changes in cannabinoid CB(1) or CB(2) receptors, the main molecular targets for the action of cannabinoids, either in the postmortem brain of patients with MS or in animal models of this disease. The present study addressed this question using the model of experimental allergic encephalomyelitis (EAE) in Lewis rats generated by inoculation of guinea pig myelin basic protein in Freund's adjuvant. After inoculation, animals were examined daily to detect the appearance of neurological signs. The first signs appeared around day 10 after inoculation, reaching the highest degree by day 13, when animals were sacrificed and their brains removed and used for analysis of CB(1) receptor binding, mRNA levels, and activation of GTP-binding proteins. CB(1) receptor binding and mRNA levels were not affected in EAE rats in brain areas such as the hippocampus, limbic structures, and cerebellum. However, there was a marked decrease in both parameters in the caudate-putamen, both in the lateral and medial parts, although this decrease did not correspond with decreases in binding in the nuclei recipient of striatal output neurons, which suggests that changes in CB(1) receptors are exclusively located in the cell bodies of striatal neurons. In addition, CB(1) receptor binding, but not mRNA levels, also decreased in the cerebral cortex, both in the deep and the superficial layers. The analysis of [(35)S]GTPgammaS binding after activation of CB(1) receptors with WIN55,212-2, a synthetic agonist, revealed that, despite the decrease in the number of CB(1) receptors in EAE rats, these were more efficiently coupled to GTP-binding protein-mediated signaling mechanisms in both the caudate-putamen and the cerebral cortex of these animals. In summary, these data suggest that the generation of EAE in Lewis rats would be associated with changes in CB(1) receptors in striatal and cortical neurons, which might be related to the alleviation of some motor signs observed after the treatment with cannabinoid receptor agonists in similar models of MS in rodents.
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PMID:Changes in cannabinoid CB(1) receptors in striatal and cortical regions of rats with experimental allergic encephalomyelitis, an animal model of multiple sclerosis. 1139 80

The purpose of these studies was to support the hypothesis that an undiscovered cannabinoid receptor exists in brain. [(35)S]GTP gamma S binding was stimulated by anandamide and WIN55212-2 in brain membranes from both CB(1)(+/+) and CB(1)(-/-) mice. In contrast, a wide variety of other compounds that are known to activate CB(1) receptors, including CP55940, HU-210, and Delta(9)-tetrahydrocannabinol, failed to stimulate [(35)S]GTP gamma S binding in CB(1)(-/-) membranes. In CB(1)(-/-) membranes, SR141716A affected both basal and anandamide- or WIN55212-2-induced stimulation of [(35)S]GTP gamma S binding only at concentrations greater than 1 microM. In CB(1)(+/+) membranes, SR141716A inhibited only 84% of anandamide and 67% of WIN55212-2 stimulated [(35)S]GTP gamma S binding with an affinity appropriate for mediation by CB(1) receptors (K(B) approximately 0.5 nM). The remaining stimulation seemed to be inhibited with lower potency (IC(50) approximately 5 microM) similar to that seen in CB(1)(-/-) membranes or in the absence of agonist. Further experiments determined that the effects of anandamide and WIN55212-2 were not additive, but that the effect of mu opioid, adenosine A1, and cannabinoid ligands were additive. Finally, assays of different central nervous system (CNS) regions demonstrated significant activity of cannabinoids in CB(1)(-/-) membranes from brain stem, cortex, hippocampus, diencephalon, midbrain, and spinal cord, but not basal ganglia or cerebellum. Moreover, some of these same CNS regions also showed significant binding of [(3)H]WIN55212-2, but not [(3)H]CP55940. Thus anandamide and WIN55212-2 seemed to be active in CB(1)(-/-) mouse brain membranes via a common G protein-coupled receptor with a distinct CNS distribution, implying the existence of an unknown cannabinoid receptor subtype in brain.
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PMID:Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. 1140 10

The CB1 cannabinoid receptor is a constitutively active receptor that can sequester G(i/o)-proteins and prevent other G(i/o)-coupled receptors from signaling (Bouaboula et al., 1997; Pan et al., 1998; Vasquez and Lewis, 1999). G-protein sequestration occurs because the population of CB1 cannabinoid receptors exists in both an inactive G-protein-precoupled RG(GDP) state and a constitutively active R*G(GTP) state. We tested the hypothesis that the distal C-terminal tail acts to prevent G-protein activation. We found that truncation of the distal C-terminal tail of the CB1 receptor (CB1-417) enhanced both the constitutive activity and the ability of the receptor to sequester G-proteins. In addition, we tested the hypothesis that the conserved aspartate (D2.50) in the second transmembrane domain of the CB1 cannabinoid receptor is crucial for constitutive activity and G-protein sequestration. We found that the mutation of aspartate to asparagine (CB1-D164N) abolished G-protein sequestration and constitutive receptor activity without disrupting agonist-stimulated activity. We conclude that the CB1-D164N mutation and the C-terminal truncation shift the population of receptors in opposite directions. The CB1-D164N mutation shifts the receptor into an inactive R state upcoupled from G-proteins, whereas the C-terminal truncation (CB1-417) shifts the receptor into the active R*G(GTP) state. Thus the distal C-terminal tail acts to constrain the receptor from activating G-proteins, whereas the aspartate (D2.50) in the second transmembrane domain stabilizes the receptor in both the inactive RG(GDP) state and the active R*G(GTP) state.
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PMID:Structural domains of the CB1 cannabinoid receptor that contribute to constitutive activity and G-protein sequestration. 1169 87

A set of 29 3-alkyl 5-arylimidazolidinediones (hydantoins) with affinity for the human cannabinoid CB(1) receptor was studied for their lipophilicity and conformational properties in order to delineate a pharmacophore. These molecules constitute a new template for cannabinoid receptor recognition, since (a) their structure differs from that of classical cannabinoid ligands and (b) antagonism is the mechanism of action of at least three compounds (20, 21, and 23). Indeed, in the [(35)S]-GTP gamma S binding assay using rat cerebellum homogenates, they behave as antagonists without any inverse agonism component. Using a set of selected compounds, experimental lipophilicity was measured by RP-HPLC and calculated by a fragmental method (CLOGP) and a conformation-dependent method (CLIP based on the molecular lipophilicity potential). These approaches revealed two models which differentiate the binding mode of nonpolar and polar hydantoins and which could explain, at least for compounds 20, 21, and 23, the mechanism of action of this new family of cannabinoid ligands.
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PMID:Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB(1) cannabinoid receptor ligands and potential antagonists: synthesis, lipophilicity, affinity, and molecular modeling. 1196 Apr 86

We investigated the cellular events linked to the induction of cannabinoid behavioural sensitization. In sensitized rats, autoradiographic binding studies with [3H]CP-55,940 showed a significant increase in cannabinoid receptor binding, specifically in the cerebellum, with no changes in the other brain areas where basal CB1-receptor expression is observed. In vitro autoradiography of CP-55,940-stimulated [35S]GTP gamma S binding provided a picture of cannabinoid receptor-mediated G protein activation. Basal [35S]GTP gamma S binding was not affected, whereas sensitized rats showed a significant increase of net [35S]GTP gamma S binding in the caudate putamen and cerebellum. Autoradiographic studies suggested that only these two areas had altered receptor functionality. We therefore focused our intracellular investigations only there, first surveying the responsiveness of the cAMP system to cannabinoids. CP-55,940 was unable to inhibit forskolin-induced cAMP accumulation in the cerebellum of sensitized animals, but no difference was observed between groups in the caudate putamen. Finally, we surveyed the levels of CREB and AP-1 binding activity, in the same two areas and found no difference in sensitized rats. The intracellular picture in sensitized rats suggests that besides the cAMP cascade, other signalling pathways may participate in the development of cannabinoid sensitization.
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PMID:Cellular mechanisms of Delta 9-tetrahydrocannabinol behavioural sensitization. 1254 69

Numerous studies have shown the existence of functional links between the endogenous cannabinoid and opioid systems. However, extensive research is still needed to elucidate the biochemical mechanisms involved in this cannabinoid-opioid interaction. Mice lacking mu- (MOR), delta- (DOR) and kappa- (KOR) opioid receptors have been generated and some specific pharmacological effects induced by cannabinoids have been reported to be modified in these animals. In order to clarify further the possible mechanisms involved in this modification of cannabinoid responses we have now evaluated the expression and functional activity of cannabinoid receptors in different brain structures in these mutant animals. For this purpose, we have performed quantitative receptor autoradiography of CB1 cannabinoid receptors and activation of GTP-binding proteins by CB1 agonists in the brain of wild-type and homozygous MOR, DOR and KOR knockout mice. There were no significant differences in the levels of CB1 receptors in the brain of MOR mutant mice. In contrast, the efficacy of CB1 receptor activation by the cannabinoid agonist WIN 55 212-2 was dramatically reduced in the caudate-putamen of MOR knockout animals. The density of CB1 receptors as well as the stimulation of GTP-binding proteins by WIN 55 212-2 were significantly increased in the substantia nigra of mice deficient in DOR. Finally, there were no major changes in the levels and functional activity of CB1 cannabinoid receptors in any brain region in KOR knockout mice. Taken together, these results indicate that deletion of MOR and DOR causes alterations in cannabinoid receptor levels and functional activity in specific brain structures, which could explain some of the functional interactions observed between these two neuronal systems.
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PMID:Cannabinoid receptor and WIN 55 212-2-stimulated [35S]-GTPgammaS binding in the brain of mu-, delta- and kappa-opioid receptor knockout mice. 1462 80

In addition to their inhibitory effects, cannabinoids also exert stimulatory activity which can be detected at the cellular level. In a previous study, we demonstrated a stimulatory effect of the synthetic cannabinoid receptor agonist desacetyllevonantradol (DALN) on Ca(2+) flux into N18TG2 neuroblastoma cells, and suggested a dual mechanism: one pathway mediated by PKA and the other one by protein kinase C (PKC). Here we studied the PKC-mediated effect of DALN on Ca(2+) influx. The stimulatory effect of DALN on Ca(2+) influx was partially blocked by the PKC inhibitor chelerythrine, by the metalloprotease inhibitor o-phenanthroline and by the MEK (mitogen-activated protein-kinase kinase, MAPK kinase) inhibitor PD98059. Immunobloting of ERK1/2 MAPK demonstrated phosphorylation by DALN, and indicated the involvement of vascular endothelial growth factor (VEGF) receptor tyrosin kinases (RTKs) in MAPK activation as it was blocked by oxindole-1. Transactivation of the VEGFR-MAPK cascade by DALN involved CB1 cannabinoid receptors coupled to Gi/Go GTP-binding proteins as it was blocked by SR141716A and by pertussis toxin (PTX). The pharmacological implications of this novel mechanism of cannabinoid activity are discussed.
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PMID:The involvement of VEGF receptors and MAPK in the cannabinoid potentiation of Ca2+ flux into N18TG2 neuroblastoma cells. 1474 3

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

The pharmacology of 3-(2-ethylmorpholino)-5,5'-di(p-bromophenyl)-imidazolidinedione (DML20), 3-(1-hydroxypropyl)-5,5'-di(p-bromophenyl)-imidazolidinedione (DML21) and 3-heptyl-5,5'-di(p-bromophenyl)-imidazolidinedione (DML23) was extended by studying affinity and GTP binding modulation on cannabinoid receptor subtypes (CB1 and CB2) from rat tissues and human cannabinoid receptors expressed in Chinese Hamster Ovary cells. Competitive binding studies indicated that DML20, DML21 and DML23 are selective ligands for cannabinoid CB1 receptors. In rat cerebellum homogenates, DML20, DML21 and DML23 were unable to influence [35S]GTPgammaS binding but competitively inhibit HU 210-induced [35S]GTPgammaS binding (pKB of 6.11 +/- 0.14, 6.25 +/- 0.06 and 5.74 +/- 0.09, respectively), indicating that they act as cannabinoid CB1 receptor neutral antagonists. However, in CHO cells homogenates expressing selectively either human cannabinoid CB1 or CB2 receptors, they behaved as inverse agonists decreasing the [35S]GTPgammaS binding, with similar efficacy. In conclusion, these derivatives exhibit different activities (neutral antagonism and inverse agonism) in the different models of cannabinoid receptors studied.
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PMID:Characterization of the pharmacology of imidazolidinedione derivatives at cannabinoid CB1 and CB2 receptors. 1521 19

CT-3 (ajulemic acid) is a synthetic analogue of a metabolite of Delta9-tetrahydrocannabinol that has reported analgesic efficacy in neuropathic pain states in man. Here we show that CT-3 binds to human cannabinoid receptors in vitro, with high affinity at hCB1 (Ki 6 nM) and hCB2 (Ki 56 nM) receptors. In a functional GTP-gamma-S assay CT-3 was an agonist at both hCB1 and hCB2 receptors (EC50 11 and 13.4 nM, respectively). In behavioural models of chronic neuropathic and inflammatory pain in the rat, oral administration of CT-3 (0.1-1 mg/kg) produced up to 60% reversal of mechanical hyperalgesia. In both models the antihyperalgesic activity was prevented by the CB1-antagonist SR141716A but not the CB2-antagonist SR144528. In the tetrad of tests for CNS activity, CT-3 (1-10 mg/kg, po) produced dose-related catalepsy, deficits in locomotor performance, hypothermia, and acute analgesia. Comparison of 50% maximal effects in the tetrad and chronic pain assays produced an approximate therapeutic index of 5-10. Pharmacokinetic analysis showed that CT-3 exhibits significant but limited brain penetration, with a brain/plasma ratio of 0.4 measured following oral administration, compared to ratios of 1.0-1.9 measured following subcutaneous administration of WIN55,212-2 or Delta9-THC. These data show that CT-3 is a cannabinoid receptor agonist and is efficacious in animal models of chronic pain by activation of the CB1 receptor. Whilst it shows significant cannabinoid-like CNS activity, it exhibits a superior therapeutic index compared to other cannabinoid compounds, which may reflect a relatively reduced CNS penetration.
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PMID:Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. 1593 83

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