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

We recently demonstrated that the selective cannabinoid receptor antagonist SR 144528 acts as an inverse agonist that blocks constitutive mitogen-activated protein kinase activity coupled to the spontaneous autoactivated peripheral cannabinoid receptor (CB2) in the Chinese hamster ovary cell line stably transfected with human CB2. In the present report, we studied the effect of SR 144528 on CB2 phosphorylation. The CB2 phosphorylation status was monitored by immunodetection using an antibody specific to the COOH-terminal CB2 which can discriminate between phosphorylated and non-phosphorylated CB2 isoforms at serine 352. We first showed that CB2 is constitutively active, phosphorylated, and internalized at the basal level. By blocking autoactivated receptors, inverse agonist SR 144528 treatment completely inhibited this phosphorylation state, leading to an up-regulated CB2 receptor level at the cell surface, and enhanced cannabinoid agonist sensitivity for mitogen-activated protein kinase activation of Chinese hamster ovary-CB2 cells. After acute agonist treatment, serine 352 was extensively phosphorylated and maintained in this phosphorylated state for more than 8 h after agonist treatment. The cellular responses to CP-55,940 were concomitantly abolished. Surprisingly, CP-55,940-induced CB2 phosphorylation was reversed by SR 144528, paradoxically leading to a non-phosphorylated CB2 which could then be fully activated by CP-55,940. The process of CP-55,940-induced receptor phosphorylation followed by SR 144528-induced receptor dephosphorylation kept recurring many times on the same cells, indicating that the agonist switches the system off but the inverse agonist switches the system back on. Finally, we showed that autophosphorylation and CP-55, 940-induced serine 352 CB2 phosphorylation involve an acidotropic GRK kinase, which does not use Gibetagamma. In contrast, SR 144528-induced CB2 dephosphorylation was found to involve an okadaic acid and calyculin A-sensitive type 2A phosphatase.
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PMID:Regulation of peripheral cannabinoid receptor CB2 phosphorylation by the inverse agonist SR 144528. Implications for receptor biological responses. 1040 Jun 64

The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.
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PMID:Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. 1044 Mar 74

The aim of this study was to characterize the activity of the cannabinoid CB2 receptor selective antagonist, N-[(1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazo le-3-carboxamide] (SR144528) in a number of biochemical assays and to look for evidence of cannabinoid CB2 receptors in the rat central nervous system. SR144528 displaced [3H]CP 55,940 ((-)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)-phenyl]-4-[3-hydroxyprop yl]cyclohexan-1-ol) from binding sites in CB2- and CB1-transfected cells (Ki = 0.67+/-0.30 and 33.0+/-5.09 nM) and from rat cerebellum and whole brain membrane homogenates (Ki = 54.7+/-9.70 and 54.8+/-7.86 nM). In the GTPgammaS binding assay, SR144528 antagonized a number of cannabinoid receptor agonists (K(B) values ranging from 26.3 to 76.6 nM) in rat cerebellar membranes and in rat whole brain membranes (K(B) = 50.8 nM). SR144528 also antagonized CP 55,940-stimulated GTPgammaS binding in a CB2-expressing cell line (K(B) = 6.34 nM). In Xenopus oocytes co-expressing the CB1 receptor and G-protein coupled inwardly rectifying K+ channels (GIRK 1/4), SR144528 antagonized WIN 55212-2((R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrolo [1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone) -stimulated K+ currents (K(B) = 558 nM). In summary, this report characterizes the cannabinoid CB2 receptor-selective cannabinoid antagonist, SR144528, and additionally suggests an absence of cannabinoid CB2 receptors in the rat central nervous system, an observation confirmed by Northern blot.
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PMID:Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528: further evidence for cannabinoid CB2 receptor absence in the rat central nervous system. 1044 34

Cannabinoid receptors are widely distributed in the nuclei of the extrapyramidal motor and mesolimbic reward systems; their exact functions are, however, not known. The aim of the present study was to characterize the effects of cannabinoids on the electrically evoked release of endogenous dopamine in the corpus striatum and the nucleus accumbens. In rat brain slices dopamine release elicited by single electrical pulses was determined by fast cyclic voltammetry. Dopamine release was markedly inhibited by the OP2 opioid receptor agonist U-50488 and the D2/D3 dopamine receptor agonist quinpirole, indicating that our method is suitable for studying presynaptic modulation of dopamine release. In contrast, the CB1/CB2 cannabinoid receptor agonists WIN55212-2 (10(-6) M) and CP55940 (10(-6)-10(-5) M) and the CB1 cannabinoid receptor antagonist SR141716A (10(-6) M) had no effect on the electrically evoked dopamine release in the corpus striatum and the nucleus accumbens. The lack of a presynaptic effect on terminals of nigrostriatal and mesolimbic dopaminergic neurons is in accord with the anatomical distribution of cannabinoid receptors: The perikarya of these neurons in the substantia nigra and the ventral tegmental area do not synthesize mRNA, and hence protein, for CB1 and CB2 cannabinoid receptors. It is therefore unlikely that presynaptic modulation of dopamine release in the corpus striatum and the nucleus accumbens plays a role in the extrapyramidal motor and rewarding effects of cannabinoids.
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PMID:Effects of cannabinoids on dopamine release in the corpus striatum and the nucleus accumbens in vitro. 1046 98

The discovery of CB1 and CB2 receptors and of endogenous agonists for these receptors has sparked renewed interest in the therapeutic potential of cannabinoids. This has led to a need for strategies that will provide a better separation of wanted from unwanted effects, particularly for CB1 receptor agonists. Possible strategies are to target CB1 receptors present on neurones outside the central nervous system or novel types or subtypes of neuronal cannabinoid receptor. This paper reviews evidence for the presence of CB1 receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors.
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PMID:Evidence for the presence of CB1 cannabinoid receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors. 1046 60

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 G protein-coupled cannabinoid receptor subtypes CB1 and CB2 have been cloned from several species. The CB1 receptor is highly conserved across species, whereas the CB2 receptor shows considerable cross-species variations. The two human receptors share only 44% overall identity, ranging from 35% to 82% in the transmembrane regions. Despite this structural disparity, the most potent cannabinoid agonists currently available are largely undiscriminating and are therefore unsatisfactory tools for investigating the architecture of ligand binding sites. However, the availability of two highly specific antagonists, SR 141716A for the CB1 receptor and SR 144528 for the CB2 receptor, has allowed us to adopt a systematic approach to defining their respective binding sites through the use of chimeric CB1 receptor/CB2 receptor constructs, coupled with site-directed mutagenesis. We identified the region encompassed by the fourth and fifth transmembrane helices as being critical for antagonist specificity. Both the wild type human receptors overexpressed in heterologous systems are autoactivated; SR 141716A and SR 144528 exhibit classical inverse agonist properties with their respective target receptors. In addition, through its interaction with the CB1 receptor SR 141716A blocks the Gi protein-mediated activation of mitogen-activated protein kinase stimulated by insulin or insulin-like growth factor I. An in-depth analysis of this discovery has led to a modified three-state model for the CB1 receptor, one of which implicates the SR 141716A-mediated sequestration of Gi proteins, with the result that the growth factor-stimulated intracellular pathways are effectively impeded.
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PMID:Cannabinoid receptor interactions with the antagonists SR 141716A and SR 144528. 1046 63

Mammalian tissues contain at least two types of cannabinoid receptor, CB1 and CB2, both coupled to G proteins. CB1 receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB2 receptors occur in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this endogenous cannabinoid system has been paralleled by a renewed interest in possible therapeutic applications of cannabinoids, for example in the management of pain and in the suppression of muscle spasticity/spasm associated with multiple sclerosis or spinal cord injury. It has also prompted the development of a range of novel cannabinoid receptor ligands, including several that show marked selectivity for CB1 or CB2 receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB1 and CB2 receptor ligands. Particular attention is paid to the binding properties of these ligands, to the efficacies of cannabinoid receptor agonists, as determined using cyclic AMP or [35S]GTPgammaS binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectively oppose the actions of CB1 or CB2 receptor agonists are also described. When administered by themselves, some of these ligands produce effects in certain tissue preparations that are opposite in direction to those produced by cannabinoid receptor agonists and the possibility that the ligands producing such inverse cannabimimetic effects are inverse agonists rather than pure antagonists is discussed.
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PMID:Pharmacology of cannabinoid receptor ligands. 1046 84

In agreement with the highly lipophilic nature of (-)-delta9-tetrahydrocannabinol, all the endogenous ligands of cannabinoid receptors identified so far are derivatives of long chain fatty acids. N- Arachidonoylethanolamine (anandamide) and some of its polyunsaturated congeners have been found in mammalian brain and shown to activate the CB1 and, with a lower efficacy, CB2 cannabinoid receptor subtypes. More recently, 2-arachidonoylglycerol (2-AG), a widespread intermediate in the metabolism of phosphoglycerides, diacylglycerols and triglycerides, was also found to activate the cannabinoid receptors. The capability of palmitoylethanolamide, an anti-inflammatory metabolite, to activate CB2-like receptors is still being debated. Here we review: 1) the metabolic pathways suggested so far to underlie the biosynthesis and inactivation of anandamide and 2-AG, and 2) the current knowledge of the chemical bases for the interactions of anandamide and 2-AG with proteins of the endogenous cannabinoid system characterized so far, i.e. the CB1 and CB2 receptor subtypes, the membrane anandamide carrier , which facilitates anandamide diffusion into cells, and the enzyme fatty acid amide hydrolase , which catalyzes anandamide and, to a certain extent, 2-AG hydrolysis in vivo.
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PMID:Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids. 1046 88

The discovery of two distinct cannabinoid receptors (CB1 and CB2) in the early 1990's has revived the research on cannabinoid antagonists. While the search for antagonists based on the structure of agonists (classical cannabinoids or aminoalkylindoles) appeared rather disappointing, the first potent cannabinoid antagonists were developed in a new chemical series: the diarylpyrazoles. Since its discovery in 1994, the selective CB1 antagonist SR 141716 has became a major pharmacological tool to elucidate the physiological role of the CB1 cannabinoid receptor and its endogenous ligand. The selective CB2 antagonist SR 144528 is expected to play the same role for the CB2 receptors, while the recent development of cannabinoid antagonists belonging to other chemical series illustrates the interest of these compounds which are now considered as interesting therapeutic targets by many pharmaceutical companies.
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PMID:The development of cannabinoid antagonists. 1046 89


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