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 CB1 cannabinoid receptor antagonist SR 141716A abolished the inhibition of Ca2+ currents by the agonist WIN 55,212-2. However, SR 141716A alone increased Ca2+ currents, with an EC50 of 32 nM, in neurons that had been microinjected with CB1 cRNA. For an antagonist to elicit an effect, some receptors must be tonically active. Evidence for tonically active CB1 receptors was seen as enhanced tonic inhibition of Ca2+ currents. Preincubation with anandamide failed to enhance the effect of SR 141716A, indicating that anandamide did not cause receptor activity. Under Ca2+-free conditions designed to block the Ca2+-dependent formation of anandamide and sn-2-arachidonylglycerol, SR 141716A again increased the Ca2+ current. The Ca2+ current was tonically inhibited in neurons expressing the mutant K192A receptor, which has no affinity for anandamide, demonstrating that this receptor is also tonically active. SR 141716A had no effect on the Ca2+ current in these neurons, but SR 141716A could still antagonize the effect of WIN 55, 212-2. Thus, the K192 site is critical for the inverse agonist activity of SR 141716A. SR 141716A appeared to become a neutral antagonist at the K192A mutant receptor. Native cannabinoid receptors were studied in male rat major pelvic ganglion neurons, where it was found that WIN 55,212-2 inhibited and SR 141716A increased Ca2+ currents. Taken together, our results demonstrate that a population of native and cloned CB1 cannabinoid receptors can exist in a tonically active state that can be reversed by SR 141716A, which acts as an inverse agonist.
Mol Pharmacol 1998 Dec
PMID:SR 141716A acts as an inverse agonist to increase neuronal voltage-dependent Ca2+ currents by reversal of tonic CB1 cannabinoid receptor activity. 985 35

Cannabinoid receptors couple to both Gs and Gi proteins and can consequently stimulate or inhibit the formation of cAMP. To test whether there is specificity among cannabinoid receptor agonists in activating Gs- or Gi-coupled pathways, the potency and intrinsic activity of various cannabinoid receptor ligands in stimulating or inhibiting cAMP accumulation were quantified. The rank order of potencies of cannabinoid receptor agonists in increasing or inhibiting forskolin-stimulated cAMP accumulation, in CHO cells expressing hCB1 receptors, was identical (HU-210 > CP-55,940 > THC > WIN-55212-2 > anandamide). However, the activities of these agonists were different in the two assays with anandamide and CP-55,940 being markedly less efficacious in stimulating the accumulation of cAMP than in inhibiting its formation. Studies examining the effects of forskolin on cannabinoid receptor mediated stimulation of adenyly cyclase also revealed differences among agonists in as much as forskolin enhanced the potency of HU-210 and CP-55,940 by approximately 100-fold but, by contrast, had no effect on the potency of WIN-55212-2 or anandamide. Taken together these findings demonstrate marked differences among cannabinoid receptor agonists in their activation of intracellular transduction pathways. This provides support for the emerging concept of agonist-specific trafficking of cellular responses and further suggests strategies for developing receptor agonists with increased therapeutic utility.
J Pharmacol Exp Ther 1998 Dec
PMID:Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. 986 68

Several analogues of the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide) were synthesized and evaluated in order to study (a) the structural requirements for high-affinity binding to the CB1 and CB2 cannabinoid receptors and (b) their hydrolytic stability toward anandamide amidase. The series reported here was aimed at exploring structure-activity relationships (SAR) primarily with regard to stereoelectronic requirements of ethanolamido headgroup for interaction with the cannabinoid receptor active site. Receptor affinities, reported as Ki values, were obtained by a standard receptor binding assay using [3H]CP-55,940 as the radioligand, while stability toward the amidase was evaluated by comparing the Ki of each analogue in the presence and absence of phenylmethanesulfonyl fluoride (PMSF), a serine protease blocker and inhibitor of anandamide amidase. Introduction of a methyl group in the 1'- and 2'-positions or substitution of the ethanolamido headgroup with a butylamido group gave analogues with vastly improved biochemical stability. This is accomplished in some cases with increased receptor affinity. Conversely, oxazolyl and methyloxazolyl headgroups led to low-affinity analogues. Substitution of the hydroxyl group with electronegative substituents such as fluoro, chloro, allyl, and propargyl groups significantly increased receptor affinity but did not influence the biochemical stability. The 2'-chloro analogue of anandamide was found to have the highest affinity for CB1. Additionally, reversing the positions of the carbonyl and NH in the amido group produces retro-anandamides possessing considerably higher metabolic stability. Replacement of the arachidonyl tail with oleyl or linoleyl results in analogues with low affinities for both receptors. All of the analogues in this study showed high selectivity for the CB1 receptor over the peripheral CB2 receptor. The most potent analogues were tested for their ability to stimulate the binding of [35S]GTPgammaS to G-proteins and were shown to be potent cannabimimetic agonists. The results are discussed in terms of pharmacophoric features affecting receptor affinity and enzymatic stability.
J Med Chem 1998 Dec 31
PMID:Novel analogues of arachidonylethanolamide (anandamide): affinities for the CB1 and CB2 cannabinoid receptors and metabolic stability. 987 5

In 1992 the discovery of the first endogenous ligand of cannabinoid receptors, anandamide, provided conclusive support to the hypothesis that an "endogenous cannabinoid regulatory system" exists in mammalian nervous tissue. Anandamide (N-arachidonoyl-ethanolamine) was the first of a series of long-chain fatty acid derivatives, including two other polyunsaturated N-acylethanolamines and 2-arachidonoyl-glycerol, found to exert cannabimimetic properties in either central or peripheral tissues. Here we review the current knowledge on the biochemical bases of the formation and inactivation of endogenous cannabinoid ligands as well as of their interaction with cannabinoid receptor subtypes.
Neurobiol Dis 1998 Dec
PMID:Biochemistry of the endogenous ligands of cannabinoid receptors. 997 73

The CB1 cannabinoid receptor in brain is a G-protein-coupled receptor that exists as a protein possessing seven transmembrane helices that span the membrane. The intracellular surface is able to interact with f1p4oteins of the Gi/o family to regulate effector proteins, including adenylate cyclase, Ca2+ channels, and K+ channels, and to stimulate the mitogen-activated protein kinase pathway. The CB1 cannabinoid receptor recognizes three classes of agonist ligands: cannabinoid, eicosanoid, and aminoalkylindole. These agonist subtypes may interact with the CB1 cannabinoid receptor by some common points of association, yet may have subtle differences in the way that they interact with the receptor protein. This may be evident in the allosteric regulation by monovalent cations and individual agonists. The juxtamembrane region of the C-terminal is able to activate G-proteins. It is proposed that conformational changes in the receptor induced by agonist ligands may alter the conformation or exposure of the juxtamembrane C-terminal region extending from helix VII.
Neurobiol Dis 1998 Dec
PMID:The CB1 cannabinoid receptor in the brain. 997 74

One of the prominent pharmacological features of drugs acting at the brain cannabinoid receptor (CB1) is the induction of alterations in motor behavior. Catalepsy, immobility, ataxia, or the impairment of complex behavioral acts are observed after acute administration of either natural and synthetic cannabinoid receptor agonists or the endogenous CB1 ligand anandamide. The dense presence of CB1 receptors in the cerebellum and in the basal ganglia, especially at the outflow nuclei (substantia nigra and the internal segment of the globus pallidus), supports the existence of an endogenous cannabinoid system regulating motor activity. In the basal ganglia, the functionality of the anandamide-CB1 system is poorly understood. Dual effects are often observed after the administration of CB1 ligands in animal models of pharmacological manipulation of basal ganglia transmitter systems, indicating that the activity of the anandamide-CB1 system depends on the ongoing activation of the different elements of the basal ganglia. This finding is in agreement with the proposed activity-dependent release of anandamide from a plasmalemma precursor. Additionally, a potential state-dependent bidirectional coupling of the CB1 receptor to the adenylate cyclase transduction system has also been described. From this perspective, the endogenous cannabinoid system can be proposed as a local regulator of neurotransmission processes within the basal ganglia. This system may serve as a counterregulatory homeostatic mechanism preserving the functional role of basal ganglia circuits in coding the serial order of events that constitute movement.
Neurobiol Dis 1998 Dec
PMID:Role of the endogenous cannabinoid system in the regulation of motor activity. 997 80

Immune modulation by cannabinoids has been widely established over the past three decades. In spite of this, the mechanism of action responsible for immune modulation and other well described biological effects attributed to cannabinoid compounds has been elusive. The identification and cloning of two novel G protein coupled receptors, CB1 and CB2, both of which bind cannabimimetic agents has served as the basis for a putative mechanism of action. CB1, which is also referred to as the central cannabinoid receptor is the primary form expressed within the central nervous system (CNS). Conversely, the peripheral cannabinoid receptor, CB2, does not appear to be expressed within the CNS but is the predominant form of the receptor expressed within the immune system. Both CB1 and CB2 negatively regulate adenylate cyclase activity through a pertussis toxin sensitive GTP-binding protein. Recent investigations addressing the mechanism by which cannabinoids disrupt leukocyte function have demonstrated that in the presence of cannabinoids the cAMP signaling cascade is markedly inhibited as evidenced by decreased adenylate cyclase and protein kinase A activity and decreased DNA binding by cAMP response element binding proteins. The focus of this discussion will be on the effects cannabinoids elicit on events within the cAMP cascade and related signaling pathways critical to the regulation of cytokine genes.
Toxicol Lett 1998 Dec 28
PMID:Inhibition of the cAMP signaling cascade via cannabinoid receptors: a putative mechanism of immune modulation by cannabinoid compounds. 1002 33

Following retroviral insertional mutagenesis we recently identified the gene encoding the peripheral cannabinoid receptor (Cb2) near a common virus integration site (VIS), Evi11. In 13 out of 105 Cas-Br-M murine leukemia virus (MuLV) induced leukemias retroviral integrations occured either in the 5' or 3' part of the Cb2 gene. The Cb2 receptor protein is 44% homologous to the central cannabinoid receptor Cb1, which belongs to the superfamily of seven transmembrane (7TM) receptors. Cb1 is mainly expressed in brain, whereas Cb2 encodes the hematopoietic form. Besides the natural cannabinoids, delta9-tetrahydrocannabinol (delta9-THC) and cannabinol, and the many synthetic agonists that have been generated, e.g CP55,940 or WIN55,212-2, several endogenous ligands have recently been identified. These include the arachidonic acid derivatives anandamide and 2-arachidonylglycerol as well as the fatty acid palmitoylethanolamide. Although in the past many studies described growth inhibitory effects of cannabinoid agonists on the in vitro proliferation of hematopoietic cells, recent studies demonstrated that activation of Cb2 may have growth stimulatory effects on blood precursor cells. We demonstrated that many murine hematopoietic growth factor (HGF) dependent cell lines also require the presence of anandamide for optimal growth in serum free culture. Thus, the Cb2 receptor may be an important regulator of normal hematopoietic growth and development. These results strengthen our finding that Cb2 is a proto-oncogene and may implicate a growth advantage for leukemia cells that aberrantly express Cb2. Here we briefly review the mechanisms and application of retroviral insertional mutagenesis in leukemic transformation in mice and discuss the role of the peripheral cannabinoid receptor in leukemia development and normal hematopoiesis.
Leuk Lymphoma 1998 Dec
PMID:The peripheral cannabinoid receptor, Cb2, in retrovirally-induced leukemic transformation and normal hematopoiesis. 1003 99

Cannabinoids have major effects on central nervous system function. Recent studies indicate that cannabinoid effects on the visual system have a retinal component. Immunocytochemical methods were used to localize cannabinoid CB1 receptor immunoreactivity (CB1R-IR) and an endocannabinoid (anandamide and 2-arachidonylglycerol) degradative enzyme, fatty acid amide hydrolase (FAAH)-IR, in the rat retina. Double labeling with neuron-specific markers permitted identification of cells that were labeled with CB1R-IR and FAAH-IR. CB1R-IR was observed in all cells that were protein kinase C-immunoreactive (rod bipolar cells and a subtype of GABA-amacrine cell) as well as horizontal cells (identified by calbindin-IR). There was also punctate CB1R-IR in the distal one-third of the inner plexiform layer (IPL) that could not be assigned to a cell type. FAAH-IR was most prominent in large ganglion cells, whose dendrites projected to a narrow band in the proximal IPL. Weaker FAAH-IR was observed in the soma of horizontal cells (identified by calbindin-IR); the soma of large, but not small, dopamine amacrine cells (identified by tyrosine hydroxylase-IR); and dendrites of orthotopic- and displaced-starburst amacrine cells (identified by choline acetyltransferase-IR) but in less than 50% of the starburst amacrine cell somata. The extensive distribution of CB1R-IR on horizontal cells and rod bipolar cells indicates a role of endocannabinoids in scotopic vision, whereas the more widespread distribution of FAAH-IR indicates a complex control of endocannabinoid release and degradation in the retina.
J Comp Neurol 1999 Dec 06
PMID:Immunocytochemical localization of cannabinoid CB1 receptor and fatty acid amide hydrolase in rat retina. 1054 Mar 59

Chronic treatment of rats with delta9-tetrahydrocannabinol (delta9-THC) results in tolerance to its acute behavioral effects. In a previous study, 21-day delta9-THC treatment in rats decreased cannabinoid activation of G proteins in brain, as measured by in vitro autoradiography of guanosine-5'-O-(3-[35S]thiotriphosphate) ([35S]GTPgammaS) binding. The present study investigated the time course of changes in cannabinoid-stimulated [35S]GTPgammaS binding and cannabinoid receptor binding in both brain sections and membranes, following daily delta9-THC treatments for 3, 7, 14, and 21 days. Autoradiographic results showed time-dependent decreases in WIN 55212-2-stimulated [35S]GTPgammaS and [3H]WIN 55212-2 binding in cerebellum, hippocampus, caudate-putamen, and globus pallidus, with regional differences in the rate and magnitude of down-regulation and desensitization. Membrane binding assays in these regions showed qualitatively similar decreases in WIN 55212-2-stimulated [35S]GTPgammaS binding and cannabinoid receptor binding (using [3H]SR141716A), and demonstrated that decreases in ligand binding were due to decreases in maximal binding values, and not ligand affinities. These results demonstrated that chronic exposure to delta9-THC produced time-dependent and region-specific down-regulation and desensitization of brain cannabinoid receptors, which may represent underlying biochemical mechanisms of tolerance to cannabinoids.
J Neurochem 1999 Dec
PMID:Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. 1058 5


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