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)

The lateral segment of the globus pallidus (GPl) is thought to be overactive in levodopa-induced dyskinesia in PD. Stimulation of cannabinoid receptors in the GPl reduces gamma-aminobutyric acid (GABA) reuptake and enhances GABA transmission and may thus alleviate dyskinesia. In a randomized, double-blind, placebo-controlled, crossover trial (n = 7), the authors demonstrate that the cannabinoid receptor agonist nabilone significantly reduces levodopa-induced dyskinesia in PD.
Neurology 2001 Dec 11
PMID:Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. 1173 35

Delta 9-tetrahydrocannabinol, the principal psychoactive component of marijuana, exerts a variety of effects on the CNS, including impaired cognitive function and neurobehavioural deficits. The mechanisms underlying these neuronal responses to tetrahydrocannabinol are unclear but may involve alterations in neuronal viability. Tetrahydrocannabinol has been shown to influence neuronal survival but the role of the cannabinoid receptors in the regulation of neuronal viability has not been fully clarified. In this study we demonstrate that tetrahydrocannabinol promotes the release of cytochrome c, activates caspase-3, promotes cleavage of the DNA repair enzyme poly-ADP ribose polymerase and induces DNA fragmentation in cultured cortical neurones. These effects of tetrahydrocannabinol were completely abrogated by the CB(1) receptor antagonist AM-251. The findings of this study demonstrate that tetrahydrocannabinol induces apoptosis in cortical neurones in a manner involving the CB1 subtype of cannabinoid receptor.
Neuroreport 2001 Dec 21
PMID:Delta 9-tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurones via activation of the CB1 receptor. 1174 22

We have previously reported that the synthetic cannabinoid receptor agonist WIN55,212-2 causes a selective reduction in paired-pulse depression of population spikes in the CA1 region of the rat hippocampal slice. This effect is consistent with the observation that activation of cannabinoid receptors inhibits GABA release in the hippocampus. We have now investigated the actions of the putative endogenous cannabinoids 2-arachidonoyl-glycerol (2-AG) and anandamide in this system. 2-AG mimicked the effect of WIN55,212-2 by selectively reducing paired-pulse depression at concentrations of 1-30 microM. In contrast, anandamide caused a selective increase in paired-pulse depression at concentrations of 1-30 microM. This effect was mimicked by the vanilloid receptor agonists capsaicin and resiniferatoxin, and blocked by the vanilloid receptor antagonist capsazepine, but not by the cannabinoid receptor antagonist AM281. These results are the first to demonstrate a clear functional vanilloid receptor-mediated effect in the hippocampus, and further, that anandamide but not 2-AG acts at these receptors to increase paired-pulse depression of population spikes.
Neuropharmacology 2001 Dec
PMID:The endogenous cannabinoid anandamide activates vanilloid receptors in the rat hippocampal slice. 1174 4

In anaesthetized rats activation of vanilloid receptors on sensory vagal nerves elicits rapid bradycardia and hypotension (Bezold-Jarisch reflex). Recent in vitro experiments revealed that the endogenous cannabinoid ligand anandamide acts as an agonist at the vanilloid VRI receptors. The present study was aimed at examining whether vanilloid VR1 receptors are involved in the cardiovascular effects of anandamide in the anaesthetized rat. Intravenous injection of anandamide, its stable analogue methanandamide and the vanilloid receptor agonist capsaicin produced a dose-dependent immediate and short-lasting decrease in heart rate and blood pressure with the following rank order of potencies: capsaicin > methanandamide > anandamide. This bradycardia was dose-dependently diminished by the selective vanilloid receptor antagonist capsazepine (0.3-3 micromol/kg) and the nonselective inhibitor of these receptors, ruthenium red (1-10 micromol/kg). Both antagonists reduced or tended to reduce the hypotension stimulated by the agonists. Following this bradycardia and hypotension (presumably evoked by the Bezold-Jarisch reflex; phase I), capsaicin, anandamide and methanandamide led to a brief vasopressor effect (phase II). Subsequently both anandamides, but not capsaicin, induced a more prolonged decrease in blood pressure (phase III). Capsazepine and ruthenium red (at doses up to 3 tmol/kg and 10 micromol/kg, respectively) failed to affect these changes in blood pressure. The cannabinoid CB1 receptor antagonist SR 141716 at 3 micromol/kg abolished the prolonged decrease in blood pressure (phase III) induced by anandamide and methanandamide, but had no effect on the reflex bradycardia and hypotension (phase I) and on the subsequent vasopressor effect (phase II) evoked by capsaicin, anandamide and methanandamide. In conclusion, the endogenous cannabinoid receptor agonist anandamide and its stable analogue methanandamide induce reflex bradycardia and hypotension (phase I) by activating the vanilloid VRI receptor. Whereas the mechanism underlying the brief vasopressor effect (phase II) is unknown, the prolonged hypotension (phase III) results from stimulation of the cannabinoid CB1 receptor.
Naunyn Schmiedebergs Arch Pharmacol 2001 Dec
PMID:Anandamide and methanandamide induce both vanilloid VR1- and cannabinoid CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats. 1177 12

The nonpsychoactive plant cannabinoid, (-)-cannabidiol, modulates in vivo responses to Delta(9)-tetrahydrocannabinol. We have found that cannabidiol can also interact with cannabinoid CB(1) receptor agonists in the mouse vas deferens, a tissue in which prejunctional cannabinoid CB(1) receptors mediate inhibition of electrically evoked contractions by suppressing noradrenaline and/or ATP release. Cannabidiol (0.316-10 microM) attenuated the ability of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) to inhibit contractions in a concentration-related, surmountable manner with a K(B) value (120.3 nM) well below its reported cannabinoid receptor CB(1)/CB(2) K(i) values. Cannabidiol (10 microM) also antagonized (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940; K(B)=34 nM) and [D-Ala(2), NMePhe(4), Gly-ol]enkephalin (DAMGO; K(B)=5.6 microM) and attenuated contractile responses to noradrenaline, phenylephrine and methoxamine but not to beta, gamma-methyleneadenosine 5'-triphosphate. At 3.16-10 microM, it increased the amplitude of evoked contractions, probably by enhancing contractile neurotransmitter release. We conclude that cannabidiol antagonizes R-(+)-WIN55212 and CP55940 by acting at prejunctional sites that are unlikely to be cannabinoid CB(1) or CB(2) receptors.
Eur J Pharmacol 2002 Dec 05
PMID:(-)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. 1245 May 75

Endogenous cannabinoids (endocannabinoids) are endogenous compounds that resemble the active ingredient of marijuana and activate the cannabinoid receptor in the brain. They mediate retrograde signaling from principal cells to both inhibitory ["depolarization-induced suppression of inhibition" (DSI)] and excitatory ("depolarization-induced suppression of excitation") afferent fibers. Transient endocannabinoid release is triggered by voltage-dependent Ca(2+) influx and is upregulated by group I metabotropic glutamate receptor activation. Here we show that muscarinic acetylcholine receptor (mAChR) activation also enhances transient endocannabinoid release (DSI) and induces persistent release. Inhibitory synapses in the rat hippocampal CA1 region of acute slices were studied using whole-cell patch-clamp techniques. We found that low concentrations (0.2-0.5 microm) of carbachol (CCh) enhanced DSI without affecting basal evoked IPSCs (eIPSCs) by activating mAChRs on postsynaptic cells. Higher concentrations of CCh (> or =1 microm) enhanced DSI and also persistently depressed basal eIPSCs, mainly by releasing endocannabinoids. Persistent CCh-induced endocannabinoid release did not require an increase in [Ca2+]i but was dependent on G-proteins. Although they were independent at the receptor level, muscarinic and glutamatergic mechanisms of endocannabinoid release shared intracellular machinery. Replication of the effects of CCh by blocking acetylcholinesterase with eserine suggests that mAChR-mediated endocannabinoid release is physiologically relevant. This study reveals a new role of the muscarinic cholinergic system in mammalian brain.
J Neurosci 2002 Dec 01
PMID:Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. 1245 Nov 19

Chronic opioid receptor (OR) activation by morphine causes distinct cellular adaptations responsible for the development of tolerance. The present study examines the effect of chronic morphine exposure on the ability of high-efficacy agonists to mediate delta-OR (DOR) and mu-OR (MOR) uncoupling and internalization, two regulatory mechanisms contributing to rapid desensitization of OR function. Chronic morphine treatment (1 microm; 72 hr) of DOR carrying neuroblastoma x glioma (NG108-15) hybrid cells, a prototypical model system frequently used to study cellular aspects of opioid tolerance, completely blocked the capacity of [d-Ala2, d-Leu5]enkephalin (DADLE) and etorphine to desensitize opioid-stimulated [35S]GTPgammaS binding and to mediate DOR internalization. Similar findings were obtained on stably DOR- and MOR-transfected human embryonic kidney (HEK) 293 cells. Chronic morphine treatment also heterologously impaired agonist regulation of non-opioid G-protein-coupled receptors, such as the m(4)-muscarinic acetylcholine receptor and the brain-type cannabinoid receptor. As a possible underlying mechanism, we found that chronic morphine treatment completely blocked agonist-induced redistribution of beta-arrestin1 in both NG108-15 and stably MOR-transfected HEK293 cells. Moreover, attenuation of beta-arrestin1 function appears to depend on persistent stimulation of MAP kinase activity during the course of chronic morphine treatment, because coincubation of the cells together with the MAP kinase blocker PD98059 fully restored beta-arrestin1 translocation and receptor internalization. These results demonstrate that chronic morphine treatment produces adaptational changes at the beta-arrestin1 level, which in turn attenuates agonist-mediated desensitization and internalization of G-protein-coupled receptors.
J Neurosci 2002 Dec 01
PMID:Chronic morphine treatment inhibits opioid receptor desensitization and internalization. 1245 Nov 20

To facilitate purification and structural characterization, the CB2 cannabinoid receptor is expressed in methylotrophic yeast Pichia pastoris. The expression plasmids were constructed in which the CB2 gene is under the control of the highly inducible promoter of P. pastoris alcohol oxidase 1 gene. A c-myc epitope and a hexahistidine tag were introduced at the C-terminal of the CB2 to permit easy detection and purification. In membrane preparations of CB2 gene transformed yeast cells, Western blot analysis detected the expression of CB2 proteins. Radioligand binding assays demonstrated that the CB2 receptors expressed in P. pastoris have a pharmacological profile similar to that of the receptors expressed in mammalian systems. Furthermore, the epitope-tagged receptor was purified by metal chelating chromatography and the purified CB2 preparations were subjected to digestion by trypsin. MALDI/TOF mass spectrometry analysis of the peptides extracted from tryptic digestions detected 14 peptide fragments derived from the CB2 receptor. ESI mass spectrometry was used to sequence one of these peptide fragments, thus, further confirming the identity of the purified receptor. In conclusion, these data demonstrated for the first time that epitope-tagged, functional CB2 cannabinoid receptor can be expressed in P. pastoris for purification.
Protein Expr Purif 2002 Dec
PMID:Expression of CB2 cannabinoid receptor in Pichia pastoris. 1246 Jul 75

We report here the synthesis and characterization of two gene constructs designed to facilitate structure/function studies of the human neuronal cannabinoid receptor, CB1. The first gene, which we call shCB1, is a synthetic gene containing unique restriction sites spaced roughly 50-100 bases apart to facilitate rapid mutagenesis and cloning. A nine amino acid epitope tag (from the rhodopsin C-terminus) is also present in the shCB1 C-terminal tail to enable detection and purification using the monoclonal antibody 1D4. We find that that the shCB1 gene can be transiently expressed in COS cells with yield of approximately 10-15 micro g receptor per 15 cm plate and is wild type like in its ability to bind cannabinoid ligands. Our confocal microscopy studies indicate shCB1 targets to the membrane of HEK293 cells and is internalized in response to agonist. To facilitate functional studies, we also made a chimera in which the C-terminus of shCB1 was fused with the N-terminus of a G-protein alpha subunit, Galphai. The shCB1/Galphai chimera shows agonist stimulated GTPgammaS binding, and thus provides a simplified way to measure agonist induced CB1 activation. Taken together, the shCB1 and shCB1/Galphai gene constructs provide useful tools for biochemical and biophysical examinations of CB1 structure, activation and attenuation.
J Pept Res 2002 Dec
PMID:Design, expression, and characterization of a synthetic human cannabinoid receptor and cannabinoid receptor/ G-protein fusion protein. 1246 12

1. Interactions between the cannabinoid system and the adenosine system were investigated in the myenteric plexus-longitudinal muscle (MPLM) of the guinea-pig ileum. 2. Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by exogenous adenosine and the adenosine receptor agonist 2-chloroadenosine. These inhibitory effects were reversed by the selective A(1) receptor antagonist DPCPX (20 nM). 3. Preincubation of the MPLM with the cannabinoid receptor agonist CP55,940 (1 nM) or the endogenous cannabinoid ligand anandamide caused a significant leftward shift in the concentration-effect curves to adenosine and 2-chloroadenosine. 4. Electrically-evoked contractions of the MPLM were inhibited in a concentration dependent manner by the adenosine uptake inhibitor dipyridamole. This inhibition was reversed by DPCPX (20 nM). 5. Pretreatment with CP55,940 (1 nM) or anandamide (10 microM) significantly reduced the inhibition produced by dipyridamole, an effect which was completely reversed by the selective CB(1) receptor ligand SR141716 (100 nM). 6. Electrically evoked adenosine release, measured in real time by means of adenosine-specific biosensors, was inhibited by CP55,940 (10 nM). This inhibition was blocked when CP55,940 was applied in the presence of SR141716 (100 nM). 7. These results confirm the presence of presynaptic CB(1) and A(1) receptors in the guinea-pig MPLM, and suggest that CB(1) receptor stimulation reduces electrically-evoked adenosine release. Overall the data raise the possibility that the cannabinoid system plays a role in the modulation of adenosine transmission in the MPLM.
Br J Pharmacol 2002 Dec
PMID:Modulation of the release of endogenous adenosine by cannabinoids in the myenteric plexus-longitudinal muscle preparation of the guinea-pig ileum. 1246 39


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