Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cannabinoids exhibit immunosuppressive actions that include inhibition of interleukin-2 production in response to a variety of T cell activation stimuli. Traditionally, the effects of these compounds have been attributed to cannabinoid receptors CB1 and CB2, both of which are expressed in mouse splenocytes. Therefore, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-H-pyrazole-3 carboxyamidehydrochloride (SR141716A), a CB1 antagonist, and N-[(1S)-endo-1,3,3,-trimethyl-bicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), a CB2 antagonist, were used to investigate the role of cannabinoid receptors in the cannabinoid-induced inhibition of phorbol ester plus calcium ionophore (PMA/Io)-stimulated interleukin-2 production by mouse splenocytes. PMA/Io-stimulated interleukin-2 production was inhibited by cannabinol, cannabidiol, and both WIN 55212-2 stereoisomers with a rank order potency of R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate (WIN 55212-2) approximately cannabidiol > S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate (WIN 55212-3) approximately cannabinol. Cannabinoid-induced inhibition of PMA/Io-stimulated interleukin-2 was not attenuated by the presence of both SR144528 and SR141716A. Using pertussis toxin to address the role of G protein-coupled receptors in this response, it was determined that pertussis toxin treatment did not attenuate cannabinol-induced inhibition of PMA/Io-stimulated interleukin-2. With the demonstration that cannabinoid-induced inhibition of PMA/Io-stimulated interleukin-2 was not mediated via CB1 or CB2, alternative targets of cannabinoids in T cells were examined. Specifically, it was demonstrated that cannabinoids elevated intracellular calcium concentration in resting splenocytes and that the cannabinol-induced elevation in intracellular calcium concentration was attenuated by treatment with both SR144528 and SR141716A. Interestingly, pretreatment of splenocytes with agents that elevate intracellular calcium concentration inhibited PMA/Io-stimulated interleukin-2 production, suggesting that an elevation in intracellular calcium concentration might be involved in the mechanism of interleukin-2 inhibition. These studies suggest that immune modulation produced by cannabinoids involves multiple mechanisms, which might be both cannabinoid receptor-dependent and -independent.
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PMID:Evidence for cannabinoid receptor-dependent and -independent mechanisms of action in leukocytes. 1280 80

Anandamide (AEA), a prominent member of the endogenous ligands of cannabinoid receptors (endocannabinoids), is known to affect several functions of brain and peripheral tissues. A potential role for AEA in skin pathophysiology has been proposed, yet its molecular basis remains unknown. Here we report unprecedented evidence that spontaneously immortalized human keratinocytes (HaCaT) and normal human epidermal keratinocytes (NHEK) have the biochemical machinery to bind and metabolize AEA, i.e. a functional type-1 cannabinoid receptor (CB1R), a selective AEA membrane transporter (AMT), an AEA-degrading fatty acid amide hydrolase (FAAH), and an AEA-synthesizing phospholipase D (PLD). We show that, unlike CB1R and PLD, the activity of AMT and the activity and expression of FAAH increase while the endogenous levels of AEA decrease in HaCaT and NHEK cells induced to differentiate in vitro by 12-O-tetradecanoylphorbol 13-acetate (TPA) plus calcium. We also show that exogenous AEA inhibits the formation of cornified envelopes, a hallmark of keratinocyte differentiation, in HaCaT and NHEK cells treated with TPA plus calcium, through a CB1R-dependent reduction of transglutaminase and protein kinase C activity. Moreover, transient expression in HaCaT cells of the chloramphenicol acetyltransferase reporter gene under control of the loricrin promoter, which contained a wild-type or mutated activating protein-1 (AP-1) site, showed that AEA inhibited AP-1 in a CB1R-dependent manner. Taken together, these data demonstrate that human keratinocytes partake in the peripheral endocannabinoid system and show a novel signaling mechanism of CB1 receptors, which may have important implications in epidermal differentiation and skin development.
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PMID:The endocannabinoid system in human keratinocytes. Evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activation protein-1, and transglutaminase. 1281 50

The study was undertaken to explore the effect of CP55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol), a drug commonly used as a CB1/CB2 cannabinoid receptor agonist, on intracellular free Ca2+ levels ([Ca2+]i) in MG63 human osteoblast-like epithelial cells. [Ca2+]i was measured in suspended cells by using the fluorescent dye fura-2 as an indicator. At concentrations between 2-20 microM, CP55,940 increased [Ca2+]i in a concentration-dependent manner with an EC50 of 8 microM. The [Ca2+] signal comprised an initial rise, a slow decay, and a sustained phase. CP55940 (10 microM)-induced [Ca2+]i signal was not altered by 5 microM of two cannabinoid receptor antagonists (AM-251, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole3-carboxamide; AM-281, 1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide). Extracellular Ca2+ removal decreased the maximum value of the Ca2+ signals by 50%. CP55,940 induced quench of fura-2 fluorescence by Mn2+ (50 microM), suggesting the presence of Ca2+ influx across the plasma membrane. CP55,940 (10 microM)-induced [Ca2+]i increase in Ca(2+)-free medium was inhibited by 84% by pretreatment with 1 microM thapsigargin, an endoplasmic reticulum Ca2+ pump inhibitor. Conversely, pretreatment with 10 microM CP55,940 in Ca(2+)-free medium abolished thapsigargin-induced [Ca2+]i increase. At 1 microM, nifedipine, verapamil, and diltiazem did not alter CP55, 940 (10 microM)-induced [Ca2+]i increase. CP55,940 (20 microM)-induced Ca2+ release was not affected when phospholipase C was inhibited by 2 microM U73122 (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino) hexyl)-1H-pyrrole-2,5-dione). CP55,940 (20 microM) did not induce acute cell death after incubation for 30 min as assayed by trypan blue exclusion. Collectively, CP55,940 induced significant [Ca2+]i increases in osteoblasts by releasing store Ca2+ from thapsigargin-sensitive stores and by causing Ca2+ entry. The CP55,940's action appears to be independent of stimulation of CB1 cannabinoid receptors.
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PMID:Effect of (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55,940) on intracellular Ca2+ levels in human osteosarcoma cells. 1281 11

Regulation of GABA release is crucial for normal brain functioning, and GABAA-mediated IPSCs are strongly influenced by repetitive stimulation and neuromodulation. However, GABA exocytosis has not been examined directly in organized tissue. Important issues remain outside the realm of electrophysiological techniques or are complicated by postsynaptic factors. For example, it is not known whether all presynaptic modulators affect release from all boutons in the same way, or whether modulator effects depend on the presence of certain types of voltage-gated calcium channels (VGCCs). To address such issues, we used confocal imaging and styryl dyes to monitor exocytosis from identified GABAergic boutons in organotypic hippocampal slice cultures. Repetitively evoked IPSCs declined more rapidly and completely than exocytosis, suggesting that depletion of filled vesicles cannot fully account for IPSC depression and underscoring the usefulness of directly imaging exocytosis. Stimulation at 10 Hz produced a transient facilitation of exocytosis that was dependent on L-type VGCCs. Using specific toxins, we found that release mediated via N-type and P-type VGCCs had similar properties. Neither baclofen nor a cannabinoid receptor agonist, CP55940, affected all boutons uniformly; they slowed release from some but completely prevented detectable release from others. Increasing stimulus frequency overcame this blockade of release. However, baclofen and CP55940 did not act identically, because only baclofen reduced facilitation and affected bouton releasing via P/Q-type VGCCs. Direct observation thus revealed novel features of GABAergic exocytosis and its regulation that would have been difficult or impossible to detect electrophysiologically. These features advance the understanding of the regulation of synapses and networks by presynaptic inhibition.
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PMID:Regulation of exocytosis from single visualized GABAergic boutons in hippocampal slices. 1462 31

Mammalian fertility absolutely depends on synchronized development of the blastocyst to the stage when it is competent to implant, and the uterus to the stage when it is receptive to implantation. However, the molecular basis for the reciprocal interaction between the embryo and the uterus remains largely unexplored. One potentially important mechanism involves signaling between an evolutionarily conserved G protein-coupled protein cannabinoid receptor, CB1, that is expressed at high levels on the surface of the trophectoderm and anandamide (N-arachi-donoylethanolamine), an endocannabinoid ligand found to be produced at higher levels by the uterus before implantation and then down-regulated at the time of implantation. Using genetic, pharmacological, and physiological approaches, we show here that anandamide within a very narrow range regulates blastocyst function and implantation by differentially modulating mitogen-activated protein kinase signaling and Ca2+ channel activity via CB1 receptors. Anandamide at a low concentration (7 nM) induces extracellular regulated kinase phosphorylation and nuclear translocation in trophectoderm cells without influencing Ca2+ channels, and renders the blastocyst competent for implantation in the receptive uterus. In contrast, anandamide at a higher concentration (28 nM) inhibits Ca2+ channel activity and blastocyst competency for implantation without influencing mitogen-activated protein kinase signaling. Besides uncovering a potentially important regulatory mechanism for synchronizing blastocyst and uterine competency to implantation, this observation has high clinical relevance, because elevated levels of anandamide induce spontaneous pregnancy loss in women.
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PMID:Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation. 1464 6

Systemic or intraventricular administration of cannabinoids causes analgesic effects, but relatively little is known for their cellular mechanism. Using brainstem slices with the mandibular nerve attached, we examined the effect of cannabinoids on glutamatergic transmission in superficial trigeminal caudal nucleus of juvenile rats. The exogenous cannabinoid receptor agonist WIN 55,212-2 (WIN), as well as the endogenous agonist anandamide, hyperpolarized trigeminal caudal neurones and depressed the amplitude of excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) monosynaptically evoked by stimulating mandibular nerves in a concentration-dependent manner. The inhibitory action of WIN was blocked or fully reversed by the CB1 receptor antagonist SR 141716A. WIN had no effect on the amplitude of miniature excitatory postsynaptic currents (mEPSCs) recorded in the presence of tetrodotoxin or cadmium. The inhibitory effect of WIN on EPSCs was greater for those with longer synaptic latency, suggesting that cannabinoids have a stronger effect on C-fibre EPSPs than on Adelta-fibre EPSPs. Ba2+ (100 microm) blocked the hyperpolarizing effect of cannabinoids, but did not affect their inhibitory effect on EPSPs. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTX) occluded the WIN-mediated presynaptic inhibition, whereas the P/Q-type Ca2+ channel blocker omega-agatoxin TK (omega-Aga) had no effect. These results suggest that cannabinoids preferentially activate CB1 receptors at the nerve terminal of small-diameter primary afferent fibres. Upon activation, CB1 receptors may selectively inhibit presynaptic N-type Ca2+ channels and exocytotic release machinery, thereby attenuating the transmitter release at the trigeminal nociceptive synapses.
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PMID:Cannabinoid-induced presynaptic inhibition at the primary afferent trigeminal synapse of juvenile rat brainstem slices. 1467 84

Addictive drugs are thought to alter normal brain function and cause the remodeling of synaptic functions in areas important to memory and reward. Excitatory transmission to the nucleus accumbens (NAc) is involved in the actions of most drugs of abuse, including cannabis. We have explored the functions of the endocannabinoid system at the prefrontal cortex-NAc synapses. Immunocytochemistry showed cannabinoid receptor (CB1) expression on axonal terminals making contacts with NAc neurons. In NAc slices, synthetic cannabinoids inhibit spontaneous and evoked glutamate-mediated transmission through presynaptic activation of presynaptic K+ channels and GABA-mediated transmission most likely via a direct presynaptic action on the vesicular release machinery. How does synaptic activity lead to the production of endogenous cannabinoids (eCBs) in the NAc? More generally, do eCBs participate in long-term synaptic plasticity in the brain? We found that tetanic stimulation (mimicking naturally occurring frequencies) of prelimbic glutamatergic afferents induced a presynaptic LTD dependent on eCB and CB1 receptors (eCB-LTD). Induction of eCB-LTD required postsynaptic activation of mGlu5 receptors and a rise in postsynaptic Ca2+ from ryanodine-sensitive intracellular Ca2+ stores. This retrograde signaling cascade involved postsynaptic eCB release and activation of presynaptic CB1 receptors. In the NAc, eCB-LTD might be part of a negative feedback loop, reducing glutamatergic synaptic strength during sustained cortical activity. The fact that this new form of LTD was occluded by an exogenous cannabinoid suggested that cannabis derivatives, such as marijuana, may alter normal eCB-mediated synaptic plasticity. These data suggest a major role of the eCB system in long-term synaptic plasticity and give insights into how cannabis derivatives, such as marijuana, alter normal eCB functions in the brain reward system.
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PMID:Exogenous and endogenous cannabinoids control synaptic transmission in mice nucleus accumbens. 1468 48

Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral pain signaling pathway, has become an area of intense research activity--largely because it represents a disorder with high unmet medical need. It is not a single disease entity, but rather includes a range of heterogeneous conditions that differ in etiology, location and initiating cause. Despite this diversity, the clinical presentation is frequently surprisingly similar, which suggests a common biological basis. Until recently, little was known of the mechanisms underlying the various neuropathic pain conditions, making the directed development of novel therapies almost impossible. However, the steady increase in our understanding of the anatomical, cellular and molecular basis of neuropathic pain, coupled with the advent of a number of experimental models of neuropathy, has permitted relatively rapid progress, and the prospects for the emergence of new, more effective therapies look very good. Gabapentin (Pfizer), which appears to act by blocking calcium channels, is the first drug to acquire widespread regulatory approval for the treatment of neuropathic pain. The Society for Medicines Research symposium held June 26, 2003, considered this treatment modality alongside other approaches to therapy, such as N-methyl-D-aspartate receptor antagonists and cannabinoid receptor agonists. The whole meeting provided an excellent description of the challenges facing neuropathic pain drug discovery--at both the research and the development phases of the value chain.
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PMID:Pharmacotherapy for neuropathic pain: progress and prospects. 1470 44

The endogenous cannabinoid system has been shown to play a crucial role in controlling neuronal excitability and synaptic transmission. In this study we investigated the effects of a cannabinoid receptor (CB-R) agonist WIN 55,212-2 (WIN) on excitatory synaptic transmission in the rat ventral tegmental area (VTA). Whole-cell patch clamp recordings were performed from VTA dopamine (DA) neurons in an in vitro slice preparation. WIN reduced both NMDA and AMPA EPSCs, as well as miniature EPSCs (mEPSCs), and increased the paired-pulse ratio, indicating a presynaptic locus of its action. We also found that WIN-induced effects were dose-dependent and mimicked by the CB1-R agonist HU210. Furthermore, two CB1-R antagonists, AM281 and SR141716A, blocked WIN-induced effects, suggesting that WIN modulates excitatory synaptic transmission via activation of CB1-Rs. Our additional finding that both AM281 and SR141716A per se increased NMDA EPSCs suggests that endogenous cannabinoids, released from depolarized postsynaptic neurons, might act retrogradely on presynaptic CB1-Rs to suppress glutamate release. Hence, we report that a type of synaptic modulation, previously termed depolarization-induced suppression of excitation (DSE), is present also in the VTA as a calcium-dependent phenomenon, blocked by both AM281 and SR141716A, and occluded by WIN. Importantly, DSE was partially blocked by the D2DA antagonist eticlopride and enhanced by the D2DA agonist quinpirole without changing the presynaptic cannabinoid sensitivity. These results indicate that the two pathways work in a cooperative manner to release endocannabinoids in the VTA, where they play a role as retrograde messengers for DSE via CB1-Rs.
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PMID:Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. 1471 37

Cannabinoids exhibit broad immune modulating activity by targeting many cell types within the immune system, including T cells, which exhibit sensitivity, as evidenced by altered activation, proliferation, and cytokine expression. As a result of the critical role calcium plays in T cell function coupled with previous findings demonstrating disruption of the calcium-regulated transcription factor, nuclear factor of activated T cells, by cannabinoid treatment, the objective of the present investigation was to perform an initial characterization of the role of the cannabinoid receptors in the regulation of the intracellular calcium concentration ([Ca(2+)](i)) by delta(9)-tetrahydrocannabinol (delta(9)-THC) in T lymphocytes. Here, we demonstrate that delta(9)-THC robustly elevates [Ca(2+)](i) in purified murine splenic T cells and in the human peripheral blood acute lymphoid leukemia (HPB-ALL) human T cell line but only minimally elevates [Ca(2+)](i) in Jurkat E6-1 (dysfunctional cannabinoid receptor 2-expressing) human T cells. Removal of extracellular calcium severely attenuated the delta(9)-THC-mediated rise in [Ca(2+)](i) in murine splenic T cells and HPB-ALL cells. Pretreatment with cannabinoid receptor antagonists, SR144528 and/or SR141716A, led to an attenuation of delta(9)-THC-mediated elevation in [Ca(2+)](i) in splenic T cells and HPB-ALL cells but not in Jurkat E6-1 cells. Furthermore, pretreatment of HPB-ALL cells with SR144528 antagonized the small rise in [Ca(2+)](i) elicited by delta(9)-THC in the absence of extracellular calcium. These findings suggest that delta(9)-THC induces an influx of extracellular calcium in resting T cells in a cannabinoid receptor-dependent manner.
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PMID:Cannabinoid receptor-mediated regulation of intracellular calcium by delta(9)-tetrahydrocannabinol in resting T cells. 1496 96


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