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

Anandamide and other polyunsaturated N-acylethanolamines (NAEs) exert biological activity by binding to cannabinoid receptors. These receptors are linked to G(i/o) proteins and their activation leads to extracellular-signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAP kinase) activation, inhibition of cAMP-dependent signalling and complex changes in the expression of various genes. Saturated and monounsaturated NAEs cannot bind to cannabinoid receptors and may thus mediate cell signalling through other targets. Here we report that both saturated/monounsaturated NAEs and anandamide (20:4(n-6) NAE) stimulate cannabinoid-receptor-independent ERK phosphorylation and activator protein-1 (AP-1)-dependent transcriptional activity in mouse epidermal JB6 cells. Using a clone of JB6 P(+) cells with an AP-1 collagen-luciferase reporter construct, we found that 16:0, 18:1(n-9), 18:1(n-7), 18:2(n-6) and 20:4(n-6) NAEs stimulated AP-1-dependent transcriptional activity up to 2-fold, with maximal stimulation at approx. 10-15 microM. Higher NAE concentrations had toxic effects mediated by alterations in mitochondrial energy metabolism. The AP-1 stimulation appeared to be mediated by ERK but not JNK or p38 signalling pathways, because all NAEs stimulated ERK1/ERK2 phosphorylation without having any effect on JNK or p38 kinases. Also, overexpression of dominant negative ERK1/ERK2 kinases completely abolished NAE-induced AP-1 activation. In contrast with 18:1(n-9) NAE and anandamide, the cannabinoid receptor agonist WIN 55,212-2 did not stimulate AP-1 activity and inhibited ERK phosphorylation. The NAE-mediated effects were not attenuated by pertussis toxin and appeared to be NAE-specific, as a close structural analogue, oleyl alcohol, failed to induce ERK phosphorylation. The data support our hypothesis that the major saturated and monounsaturated NAEs are signalling molecules acting through intracellular targets without participation of cannabinoid receptors.
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PMID:Cannabinoid-receptor-independent cell signalling by N-acylethanolamines. 1169 93

The CB1 cannabinoid receptor has been shown to couple with pertussis toxin (PTX)-sensitive Gi/o proteins and inhibit adenylyl cyclase. However, in certain conditions, CB1 mediates adenylyl cyclase activation, possibly through Gs-type G proteins. In rat B103 neuroblastoma cells in which CBI gene was endogenously expressed, anandamide inhibited forskolin-induced cAMP accumulation via PTX-sensitive pathways. When CB1 was heterologously over-expressed using a retroviral transfer, high concentrations of anandamide increased forskolin-induced cAMP accumulation, and this effect was more prominent when cells were pretreated with PTX. In CB1-over-expressing B103 cells, anandamide induced cell rounding via a PTX-insensitive/Rho kinase inhibitor-sensitive pathway. These results suggest that the CB1 receptor could couple with G proteins that activate Rho (possibly G12/13) as well as Gi/o and Gs.
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PMID:Anandamide-induced neuroblastoma cell rounding via the CB1 cannabinoid receptors. 1197 52

We studied the delay in gastric emptying and gastrointestinal transit induced by the cannabinoid receptor agonists (+)-WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) and CP 55,940 ((-)-cis-3[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol), as prevented by the selective cannabinoid CB(1)-receptor antagonist SR141716 ((N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide)) in rats after systemic or central drug administration. Oral SR141716 showed comparable potency (ID(50) range 1.0-3.9 mg/kg) in antagonizing gastric emptying and gastrointestinal transit delay by (+)-WIN 55,212-2 or CP 55,940. Gastric emptying and gastrointestinal transit delay after intracerebroventricular (i.c.v.) (+)-WIN 55,212-2 was prevented by oral or i.c.v. SR141716, but i.c.v. SR141716 did not significantly reduce the effect of i.p. (+)-WIN 55,212-2. Pertussis toxin prevented the delaying action of i.c.v. (+)-WIN 55,212-2 on both gastric emptying and gastrointestinal transit, but had no effect on (+)-WIN 55,212-2 i.p. These findings are consistent with a primary role of peripheral cannabinoid CB(1) receptor mechanisms in gastrointestinal transit delay by specific agonists.
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PMID:Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors. 1217 12

Upon activation, brain microglial cells release proinflammatory mediators, such as TNFalpha, which may play an important role in eliciting neuroinflammatory processes causing brain damage. As cannabinoids have been reported to exert anti-inflammatory and neuroprotective actions in the brain, we here examined the effect of both synthetic and endogenous cannabinoids on TNFalpha release elicited by bacterial endotoxin lypopolysaccharide (LPS) in cultured microglia. Exposure of primary cultures of rat cortical microglial cells to LPS significantly stimulated TNFalpha mRNA expression and release. The endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG), as well as the synthetic cannabinoids (+)WIN 55,212-2, CP 55,940, and HU210, inhibited in a concentration-dependent manner (1-10 microM) the LPS-induced TNFalpha release. Unlike the high-affinity cannabinoid receptor agonist (+)WIN 55,212-2, the low-affinity stereoisomer (-)WIN 55,212-2 did not exert any significant inhibition on TNFalpha release. Given this stereoselectivity, the ability of (+)WIN 55,212-2 to inhibit LPS-induced TNFalpha release from microglia is most likely receptor-mediated. By RT-PCR we found that the two G(i/o) protein-coupled cannabinoid receptors (type 1 and 2) are both expressed in microglial cultures. However, selective antagonists of type 1 (SR141716A and AM251) and type 2 (SR144528) cannabinoid receptors did not affect the effect of (+)WIN 55,212-2. Consistent with this finding is the observation that the ablative effect of (+)WIN 55,212-2 on LPS-evoked release of TNFalpha was not sensitive to the G(i/o) protein inactivator pertussis toxin. In addition, the cAMP elevating agents dibutyryl cAMP and forskolin both abolished LPS-induced TNFalpha release, thus rendering unlikely the possibility that (+)WIN 55,212-2 could ablate TNFalpha release through the inhibition of adenylate cyclase via the G(i)-coupled cannabinoid receptors type 1 and 2. In summary, our data indicate that both synthetic and endogenous cannabinoids inhibit LPS-induced release of TNFalpha from microglial cells. By showing that such effect does not appear to be mediated by either CB receptor type 1 or 2, we provide evidence suggestive of the existence of yet unidentified cannabinoid receptor(s) in brain microglia.
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PMID:Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. 1250 6

In the present study, we observed evidence of cross-talk between the cannabinoid receptor CB1 and the orexin 1 receptor (OX1R) using a heterologous system. When the two receptors are co-expressed, we observed a major CB1-dependent enhancement of the orexin A potency to activate the mitogen-activated protein kinase pathway; dose-responses curves indicated a 100-fold increase in the potency of orexin-mediated mitogen-activated protein kinase activation. This effect required a functional CB1 receptor as evidenced by the blockade of the orexin response by the specific CB1 antagonist, N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (SR141716), but also by pertussis toxin, suggesting that this potentiation is Gi-mediated. In contrast to OX1R, the potency of direct activation of CB1 was not affected by co-expression with OX1R. In addition, electron microscopy experiments revealed that CB1 and OX1R are closely apposed at the plasma membrane level; they are close enough to form hetero-oligomers. Altogether, for the first time our data provide evidence that CB1 is able to potentiate an orexigenic receptor. Considering the antiobesity effect of SR141716, these results open new avenues to understand the mechanism by which the molecule may prevent weight gain through functional interaction between CB1 and other receptors involved in the control of appetite.
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PMID:Hypersensitization of the Orexin 1 receptor by the CB1 receptor: evidence for cross-talk blocked by the specific CB1 antagonist, SR141716. 1269 Jan 15

Beta(2)-adrenergic receptors (beta(2)-AR) and CB1 cannabinoid receptors share the property of being constitutively active. The CB1 cannabinoid receptor can also sequester G(i/o) proteins; however, it is not known whether the beta(2)-AR can also sequester G proteins. Beta(2)-ARs were heterologously expressed in rat superior cervical ganglion neurons by microinjection of cDNA and studied using the patch-clamp technique. The beta-AR agonist isoproterenol increased the Ca(2+) current 25.9+/-1.6% in neurons microinjected with 100 ng/microl beta(2)-AR cDNA but was without effect on control neurons. Pretreatment with cholera toxin (CTX) abolished the effect of isoproterenol, indicating coupling via G(s) proteins. In neurons microinjected with 200 ng/microl beta(2)-AR cDNA, isoproterenol had the opposite effect of inhibiting the Ca(2+) current 36.5+/-2.0%. Inhibition of the Ca(2+) current was sensitive to pertussis toxin, indicating beta(2)-AR coupling to G(i/o) proteins. Pretreatment with CTX resulted in a greater 54+/-3.8% inhibition of the Ca(2+) current, indicating that G(s) coupling masks the full effect of G(i/o) coupling. Expression of beta(2)-ARs abolished signaling by G(s)-coupled receptors for vasoactive intestinal polypeptide (VIP). VIP inhibited the Ca(2+) current 49.5+/-0.5% in control neurons but had no effect in neurons expressing beta(2)-ARs. In contrast, expression of beta(2)-ARs had no effect on signaling by the G(i/o)-coupled alpha(2)-adrenergic receptor. This study demonstrates that the beta(2)-AR couples to both G(s) and G(i/o) proteins but specifically sequesters G(s) proteins, preventing their interaction with another G(s)-coupled receptor. beta(2)-adrenergic receptors thus have the potential to prevent other G(s)-coupled receptors from transducing their biological signals.
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PMID:The beta2-adrenergic receptor specifically sequesters Gs but signals through both Gs and Gi/o in rat sympathetic neurons. 1271 Sep 70

2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2) and has been shown to exhibit a variety of cannabimimetic activities in vitro and in vivo. Recently, we proposed that 2-arachidonoylglycerol is the true endogenous ligand for the cannabinoid receptors, and both receptors (CB1 and CB2) are primarily 2-arachidonoylglycerol receptors. The CB1 receptor is assumed to be involved in the attenuation of neurotransmission. On the other hand, the physiological roles of the CB2 receptor, which is abundantly expressed in several types of leukocytes such as macrophages, still remain unknown. In this study, we examined the effects of 2-arachidonoylglycerol on the motility of HL-60 cells differentiated into macrophage-like cells. We found that 2-arachidonoylglycerol induces the migration of differentiated HL-60 cells. The migration induced by 2-arachidonoylglycerol was blocked by treatment of the cells with either SR144528, a CB2 receptor antagonist, or pertussis toxin, suggesting that the CB2 receptor and Gi/Go are involved in the 2-arachidonoylglycerol-induced migration. Several intracellular signaling molecules such as Rho kinase and mitogen-activated protein kinases were also suggested to be involved. In contrast to 2-arachidonoylglycerol, anandamide, another endogenous cannabinoid receptor ligand, failed to induce the migration. The 2-arachidonoylglycerol-induced migration was also observed for two other types of macrophage-like cells, the U937 cells and THP-1 cells, as well as human peripheral blood monocytes. These results strongly suggest that 2-arachidonoylglycerol induces the migration of several types of leukocytes such as macrophages/monocytes through a CB2 receptor-dependent mechanism thereby stimulating inflammatory reactions and immune responses.
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PMID:2-arachidonoylglycerol induces the migration of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes through the cannabinoid CB2 receptor-dependent mechanism. 1271 5

The effect of the endogenous cannabinoid ligand anandamide on the function of the cloned alpha7 subunit of the nicotinic acetylcholine (ACh) receptor expressed in Xenopus oocytes was investigated by using the two-electrode voltage-clamp technique. Anandamide reversibly inhibited nicotine (10 microM) induced-currents in a concentration-dependent manner (10 nM to 30 microM), with an IC50 value of 229.7 +/- 20.4 nM. The effect of anandamide was neither dependent on the membrane potential nor meditated by endogenous Ca2+ dependent Cl- channels since it was unaffected by intracellularly injected BAPTA and perfusion with Ca2+-free bathing solution containing 2 mM Ba2+. Anandamide decreased the maximal nicotine-induced responses without significantly affecting its potency, indicating that it acts as a noncompetitive antagonist on nicotinic acetylcholine (nACh) alpha7 receptors. This effect was not mediated by CB1 or CB2 receptors, as neither the selective CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR 141716A) nor CB2 receptor antagonist N-((1S)-endo-1,3,3-trimethyl-bicyclo-heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR 144528) reduced the inhibition by anandamide. In addition, inhibition of nicotinic responses by anandamide was not sensitive to either pertussis toxin treatment or to the membrane permeable cAMP analog 8-Br-cAMP (0.2 mM). Inhibitors of enzymes involved in anandamide metabolism including phenylmethylsulfonyl fluoride, superoxide dismutase, and indomethacin, or the anandamide transport inhibitor AM404 did not prevent anandamide inhibition of nicotinic responses, suggesting that anandamide itself acted on nicotinic receptors. In conclusion, these results demonstrate that the endogenous cannabinoid anandamide inhibits the function of nACh alpha7 receptors expressed in Xenopus oocytes in a cannabinoid receptor-independent and noncompetitive manner.
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PMID:The endogenous cannabinoid anandamide inhibits alpha7 nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes. 1276 52

(1) We examined A3 adenosine and CB1 cannabinoid receptor-coupled signaling pathways regulating Cl(-) current in a human nonpigmented ciliary epithelial (NPCE) cell line. (2) Whole-cell patch-clamp recordings demonstrated that the A3 receptor agonist, IB-MECA, activates an outwardly rectifying Cl(-)current (I(Cl,Aden)) in NPCE cells, which was inhibited by the adenosine receptor antagonist, CGS-15943 or by the protein kinase C (PKC) activator, phorbol 12,13 dibutyrate (PDBu). (3) Treatment of NPCE cells with pertussis-toxin (PTX), or transfection with the COOH-terminus of beta-adrenergic receptor kinase (ct-betaARK), inhibited I(Cl,Aden). The phosphatidyl inositol 3-kinase (PI3K) inhibitor, wortmannin, had no effect on I(Cl,Aden); however, the mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, inhibited I(Cl,Aden). (4) Reverse transcription-polymerase chain reaction experiments and immunocytochemistry confirmed mRNA and protein expression for the CB1 receptor in NPCE cells, and the CB1 receptor agonist, Win 55,212-2, activated a PDBu-sensitive Cl(-) current (I(Cl,Win)). (5) Transfection of NPCE cells with the human CB1 (hCB1) receptor, increased I(Cl,Win), consistent with increased receptor expression, and I(Cl,Win) in hCB1 receptor-transfected cells was decreased after application of a CB1 receptor inverse agonist, SR 141716. (6) Constitutive activity for CB1 receptors was not significant in NPCE cells as transfection with hCB1 receptors did not increase basal Cl(-) current, nor was basal current inhibited by SR 141716. (7) I(Cl,Win) was inhibited by PTX preincubation, by transfection with ct-betaARK and by the MEK inhibitor, PD98059, but unaffected by the PI3K inhibitor, wortmannin. (8) We conclude that both A3 and CB1 receptors activate a PKC-sensitive Cl(-) current in human NPCE cells via a G(i/o)/Gbetagamma signaling pathway, in a manner independent of PI3K but involving MAPK.
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PMID:A3 adenosine and CB1 receptors activate a PKC-sensitive Cl- current in human nonpigmented ciliary epithelial cells via a G beta gamma-coupled MAPK signaling pathway. 1278 7

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


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