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 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

The effects of cannabinoid drugs on cAMP production were examined in mammalian brain. The cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3,-d,e-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone (WIN55,212-2) decreased forskolin-induced cAMP accumulation in a concentration-dependent manner (10(-8)-10(-5) M) in membranes from several rat and human brain regions, this effect being antagonized by 10(-5) M N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). Furthermore, high micromolar concentrations of SR141716A evoked a dose-dependent increase in basal cAMP in rat cerebellum and cortex, as well as in human frontal cortex. This effect was antagonized by WIN55,212-2 and abolished by N-ethylmaleimide, consistent with the involvement of cannabinoid CB(1) receptors through the activation of G(i/o) proteins. These results suggest a ligand-independent activity for cannabinoid CB(1) receptor signaling cascade in mammalian brain.
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PMID:Cannabinoid receptor antagonism and inverse agonism in response to SR141716A on cAMP production in human and rat brain. 1204 90

NF-kappaB is a transcriptional regulator that plays a key role in immunity, inflammation and programmed cell death. We generated a PC12 cell line termed PC12kappaBluc that contains an integrated NF-kappaB-responsive reporter gene to directly measure NF-kappaB activity. The "classical" activators of NF-kappaB, phorbol 12-O-tetradecanoate-13-acetate and tumor necrosis factor alpha, strongly induced NF-kappaB activity in PC12kappaBluc cells. Activation of NF-kappaB could be attenuated by preincubating the cells with the cAMP analogue dbcAMP or via expression of the superrepressor IkappaBalphaS32A/S36A. PC12kappaBluc cells were subjected to several apoptotic paradigms, including treatment with 6-hydroxydopamine, H2O2, K2Cr2O7, MnCl2, C2-ceramide or the cannabinoid receptor-1 agonist CP55,940. A simultaneous measurement of the NF-kappaB activity revealed that only administration of 6-hydroxydopamine or CP55,940 increased NF-kappaB activity. Using pharmacological and genetic strategies to attenuate NF-kappaB transcriptional activity, we demonstrate that the elevation of NF-kappaB activity by 6-hydroxydopamine and CP55,940 is not an integral part of the apoptotic signaling cascade in PC12 cells.
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PMID:Lack of correlation between NF-kappaB activation and induction of programmed cell death in PC12 pheochromocytoma cells treated with 6-hydroxydopamine or the cannabinoid receptor 1-agonist CP55,940. 1214 1

The effect of cannabinoid on the tyrosine phosphorylation of focal adhesion kinase (FAK) and focal adhesion kinase-related non-kinase (FRNK) was investigated in differentiated mouse neuroblastoma N1E-115 cells. HU-210, a potent cannabinoid agonist, elicited a time-dependent enhancement of tyrosine phosphorylation of FRNK, but not FAK. Pretreatment of cells with antisense oligodeoxynucleotide targeting CB1 cannabinoid receptor abolished HU-210-induced FRNK tyrosine phosphorylation. In addition, pretreatment of cells with 8-Br-cAMP also blocked HU-210-induced FRNK tyrosine phosphorylation. These data demonstrated that HU-210 induces FRNK tyrosine phosphorylation by activating G(i)-coupled CB1 cannabinoid receptor in N1E-115 cells. This newly discovered, cannabinoid-induced FRNK tyrosine phosphorylation might be a novel mechanism for cannabinoid-induced functional changes.
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PMID:CB1 cannabinoid receptor-mediated tyrosine phosphorylation of focal adhesion kinase-related non-kinase. 1216 81

Anandamide (AEA), a prominent member of the endogenous ligands of cannabinoid receptors (endocannabinoids), is known to adversely affect female fertility. However, a potential role of AEA in male reproductive functions is unknown. Here we report evidence that immature mouse Sertoli cells have the biochemical tools to bind and inactivate AEA, i.e. a functional type-2 cannabinoid receptor (CB2R), a selective AEA membrane transporter, and an AEA-degrading enzyme fatty acid amide hydrolase. We show that, unlike CB2R, the activity of AEA membrane transporter and the activity and expression of FAAH decrease, whereas the apoptosis-inducing activity of AEA increases with age during the neonatal period. We also show that FSH reduces the apoptotic potential of AEA, but not that of its nonhydrolyzable analog methanandamide. Concomitantly, FSH enhances FAAH activity in a manner dependent on mRNA transcription and protein synthesis and apparently involving cAMP. These data demonstrate that Sertoli cells partake in the peripheral endocannabinoid system, and that FSH reduces the apoptotic potential of AEA by activating FAAH. Taken together, it can be suggested that the endocannabinoid network plays a role in the hormonal regulation of male fertility.
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PMID:Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells. 1248 26

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

We investigated the cellular events linked to the induction of cannabinoid behavioural sensitization. In sensitized rats, autoradiographic binding studies with [3H]CP-55,940 showed a significant increase in cannabinoid receptor binding, specifically in the cerebellum, with no changes in the other brain areas where basal CB1-receptor expression is observed. In vitro autoradiography of CP-55,940-stimulated [35S]GTP gamma S binding provided a picture of cannabinoid receptor-mediated G protein activation. Basal [35S]GTP gamma S binding was not affected, whereas sensitized rats showed a significant increase of net [35S]GTP gamma S binding in the caudate putamen and cerebellum. Autoradiographic studies suggested that only these two areas had altered receptor functionality. We therefore focused our intracellular investigations only there, first surveying the responsiveness of the cAMP system to cannabinoids. CP-55,940 was unable to inhibit forskolin-induced cAMP accumulation in the cerebellum of sensitized animals, but no difference was observed between groups in the caudate putamen. Finally, we surveyed the levels of CREB and AP-1 binding activity, in the same two areas and found no difference in sensitized rats. The intracellular picture in sensitized rats suggests that besides the cAMP cascade, other signalling pathways may participate in the development of cannabinoid sensitization.
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PMID:Cellular mechanisms of Delta 9-tetrahydrocannabinol behavioural sensitization. 1254 69

It has been suggested that the cannabinoid receptor type 1 (CB1), a G protein-coupled receptor, is internalized after agonist binding and activation of the second messenger pathways. It is proposed that phosphorylation enhances the down-regulation of the CB1 receptor, thus contributing to tolerance. Alterations in phosphorylation of proteins in the signal transduction cascade after CB1receptor activation could also alter tolerance to cannabinoids. We addressed our hypothesis by evaluating the role of several kinases in antinociceptive tolerance to Delta(9)-tetrahydrocannabinol (THC). We evaluated cAMP-dependent protein kinase (PKA) using KT5720, a PKA inhibitor; protein kinase C (PKC) using bisindolylmaleimide I, HCl (bis), a PKC inhibitor; cGMP-dependent protein kinase (PKG) using KT5823, a PKG inhibitor; beta-adrenergic receptor kinase (beta-ARK) using low molecular weight heparin (LMWH), a beta-ARK inhibitor; and phosphatidylinositol-3 kinase (PI3-K) using 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a PI3-K inhibitor and PP1, a Src family tyrosine kinase inhibitor. The cAMP analog used was dibutyryl-cAMP and the cGMP analog used was dibutyryl-cGMP. Our data indicate that selective kinases may be involved in cannabinoid tolerance. Mice and rats were rendered tolerant to Delta(9)-THC. The PKG inhibitor KT5823, the beta-ARK inhibitor LMWH, the PI3-K inhibitor LY294002, and inhibition of PKC by bis had no effect on tolerance. At a higher dose, bis attenuated the antinociceptive effect of delta(9)-THC in nontolerant mice. PP1, the Src family tyrosine kinase inhibitor, and KT5720, the PKA inhibitor, reversed THC-induced tolerance. In addition, inhibition of PKA reversed a decrease in dynorphin release shown to accompany THC tolerance in rats. These data support a role for PKA and Src tyrosine kinase in phosphorylation events in delta(9)-THC-tolerant mice.
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PMID:The role of several kinases in mice tolerant to delta 9-tetrahydrocannabinol. 1260 57

Brucella spp. are intramacrophage pathogens that induce chronic infections in a wide range of mammals, including domestic animals and humans. Therefore, the macrophage response to infection has important consequences for both the survival of phagocytosed bacteria and the further development of host immunity. However, very little is known about the macrophage cell signaling pathways initiated upon infection and the virulence strategy that Brucella use to counteract these responses and secure their survival. In a previous study, we have shown that macrophages activated by SR141716A, a ligand of the cannabinoid receptor CB1, acquired the capacity to control Brucella and observed that the CB1 receptor-triggering engages the microbicidal activity of phagocytes. To analyze the perturbation of cell signaling pathway during macrophage infection by Brucella, we hypothesized that SR141716A provides cell signaling that interferes with the bacterial message leading to inhibition of macrophage functions. As CB1 receptor belongs to the family of G protein-linked receptors, we explored the cAMP signaling pathway. In this study, we show that the CB1 ligand inhibited the bacteria-induced cell signaling. Taking advantage of this result, we then demonstrated that Brucella infection elicited a rapid activation of the cAMP/protein kinase A pathway. This activation resulted in a prolonged phosphorylation of the transcription factor CREB. We finally demonstrate that the activation of the cAMP/protein kinase A pathway is crucial for the survival and establishment of Brucella within macrophages. For the first time in phagocytes, we thus characterized a primordial virulence strategy of Brucella involving the host signaling pathway, a novel point of immune intervention of this virulent pathogen.
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PMID:Subversion and utilization of the host cell cyclic adenosine 5'-monophosphate/protein kinase A pathway by Brucella during macrophage infection. 1275 40

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


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