UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cannabinoid receptors expressed in the mouse neuroblastoma X rat glioma NG108-15 cell and the rat pituitary tumor GH4C1 cell were determined by polymerase chain reaction, dideoxysequencing and pharmacologically. The CB1 but not the CB2 or CB1A cannabinoid receptor was found in both cell lines. The cDNA identified in GH4C1 cells corresponds to the rat CB1 receptor. Interestingly, NG108-15 cells express two distinct cDNAs, one corresponds to the rat and the other to the mouse CB1 receptor. The newly developed CB1 receptor selective antagonist SR141716A was found to reverse cannabinoid agonist (WIN55212-2 or CP55940)-induced adenylyl cyclase inhibition. These results provide more direct evidence that the CB1 receptor is mediating the pharmacological actions of cannabinoids in NG108-15 and GH4C1 cells.
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PMID:Determination of the cannabinoid receptors in mouse x rat hybridoma NG108-15 cells and rat GH4C1 cells. 883 54

The predominant animal model in which the pharmacology of cannabinoids is studied is the mouse. Nonetheless, the structure and functional expression of the mouse cannabinoid receptor (CB1) gene have not been reported. We have cloned and expressed the gene for the mouse CB1 receptor and compared its properties with those of native mouse CB1 receptors in brain and N18TG2 neuroblastoma cells. The mouse CB1 gene was isolated from a mouse 129 strain genomic library. Sequence analysis of a 6-kb BamHI fragment of the mouse CB1 genomic clone indicates 95% nucleic acid identity between mouse and rat (99.5% amino acid identity) and 90% nucleic acid identity (97% amino acid identity) between mouse and human. Examination of the 5' untranslated sequence of the mouse CB1 genomic clone revealed a splice junction site approximately 60 bp upstream from the translation start site, indicating the possibility of splice variants of the CB1 receptors. The coding region of the mouse CB1 receptor was stably expressed in 293 cells, and binding by [3H]SR 141716A and [3H]CP-55,940 was determined. The Bmax and Kd values obtained with [3H]SR 141716A (921 +/- 58 fmol/mg and 0.73 +/- 0.13 nM, respectively) were similar to those of native mouse CB1 receptors in brain (Bmax of 1.81 +/- 0.44 pmol/mg, Kd of 0.16 +/- 0.01 nM) and N18TG2 cells (Bmax of 197 +/- 29 fmol/mg, Kd of 0.182 +/- 0.08 nM). The mouse CB1 receptor genomic clone will be a useful tool for studying the function and regulation of the CB1 receptor in mice.
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PMID:Isolation and expression of a mouse CB1 cannabinoid receptor gene. Comparison of binding properties with those of native CB1 receptors in mouse brain and N18TG2 neuroblastoma cells. 903 53

Numerous reports have suggested that increased synthesis of eicosanoids is a significant effect of cannabinoids in several models including the human. To address the question of receptor mediation in this process we have carried out experiments using oligonucleotides that are antisense to the CB1 and to the CB2 receptors. We have synthesized sense, antisense and random oligonucleotide probes to test for receptor involvement in THC stimulation of arachidonic acid release in three cell lines of both central and peripheral origin. Treatment of N18 mouse neuroblastoma cells with the CB1 antisense probe, at two concentrations, resulted in a dramatic decrease of THC stimulated arachidonate release while treatment with antisense CB2 was less effective. Synthesis of the novel eicosanoid, anandamide, was also reduced by antisense CB1 but not by antisense CB2. Western blot analysis indicated a decreased level of CB1 in CB1 antisense treated cells. The CB1 antagonist, SR141716A, was effective in reducing the THC elevated levels of free arachidonate in these cells in agreement with the antisense data. In the macrophage line, RAW 264.7, we found that while the sense, the random and the CB1 antisense oligonucleotides were ineffective, the CB2 antisense probe gave significant reductions of the THC induced response. The CB2 probe was also effective in reducing the release of arachidonate in WI-38 human lung fibroblasts. These findings support the idea of a receptor mediated process for cannabinoid stimulation of eicosanoid synthesis.
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PMID:Receptor mediation in cannabinoid stimulated arachidonic acid mobilization and anandamide synthesis. 912 78

Fatty acid amide hydrolase (FAAH) catalyzes the hydrolysis of bioactive fatty acid amides and esters such as the endogenous cannabinoid receptor ligands, anandamide (N-arachidonoyl-ethanolamine) and 2-arachidonoylglycerol, and the putative sleep inducing factor cis-9-octadecenoamide (oleamide). Most FAAH blockers developed to date also inhibit cytosolic phospholipase A2 (cPLA2) and/or bind to the CB1 cannabinoid receptor subtype. Here we report the finding of four novel FAAH inhibitors, two of which, malhamensilipin A and grenadadiene, were screened out of a series of thirty-two different algal natural products, and two others, arachidonoylethylene glycol (AEG) and arachidonoyl-serotonin (AA-5-HT) were selected out of five artificially functionalized polyunsaturated fatty acids. When using FAAH preparations from mouse neuroblastoma N18TG2 cells and [14C]anandamide as a substrate, the IC50s for these compounds ranged from 12.0 to 26 microM, the most active compound being AA-5-HT. This substance was also active on FAAH from rat basophilic leukaemia (RBL-2H3) cells (IC50 = 5.6 microM), and inhibited [14C]anandamide hydrolysis by both N18TG2 and RBL-2H3 intact cells without affecting [14C]anandamide uptake. While AEG behaved as a competitive inhibitor and was hydrolyzed to arachidonic acid (AA) by FAAH preparations, AA-5-HT was resistant to FAAH-catalyzed hydrolysis and behaved as a tight-binding, albeit non-covalent, mixed inhibitor. AA-5-HT did not interfere with cPLA2-mediated, ionomycin or antigen-induced release of [3H]AA from RBL-2H3 cells, nor with cPLA2 activity in cell-free experiments. Finally, AA-5-HT did not activate CB1 cannabinoid receptors since it acted as a very weak ligand in in vitro binding assays, and, at 10-15 mg/kg body weight, it was not active in the 'open field', 'hot plate' and rectal hypothermia tests carried out in mice. Conversely AEG behaved as a cannabimimetic substance in these tests as well as in the 'ring' immobility test where AA-5-HT was also active. AA-5-HT is the first FAAH inhibitor reported to date which is inactive both against cPLA2 and at CB1 receptors, whereas AEG represents a new type of cannabinoid receptor agonist.
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PMID:Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase. 970 57

N18TG2 neuroblastoma cells co-express delta-opioid and CB1-cannabinoid receptors. Both receptors are negatively coupled to adenylyl cyclase through pertussis toxin-sensitive GTP-binding proteins. In the present study, we confirmed the independent activity of opioid and cannabinoid agonists, and investigated chronic interactions between the two signal transduction pathways in these cells. Opioid and cannabinoid agonists stimulated [35S]guanosine-5'-O-(3-thiotriphosphate) binding to N18TG2 membranes. When the opioid agonist etorphine and the cannabinoid agonist desacetyllevonantradol (DALN) were applied together, the stimulation was similar to the arithmetic sum of the two separate effects. This additivity existed even after partial ablation of the G-proteins reservoir with a low concentration of pertussis toxin, indicating that opioid and cannabinoid receptors activate different pools of G-proteins in N18TG2 cells. Chronic treatment of the cells with either opioid or cannabinoid agonists induced desensitization to the respective drug. In addition, asymmetric cross-desensitization was found: while long-term exposure to DALN induced homologous desensitization, and did not reduce the effect of etorphine, long-term exposure to etorphine attenuated the cannabinoid activation of G-proteins. Chronic exposure to either DALN or etorphine not only induced desensitization, but also elevated the basal activity of G-proteins in the exposed cells. The combination of the two drugs did not yield an additive activation, suggesting that chronic exposure of N18TG2 cultures to cannabinoid and opioid agonists modified a common responding element within the cells. This work presents the N18TG2 neuroblastoma as a suitable experimental model to study the molecular mechanism(s) underlying chronic interactions between opioid and cannabinoid drugs.
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PMID:Independence of, and interactions between, cannabinoid and opioid signal transduction pathways in N18TG2 cells. 973 2

A CB1 cannabinoid receptor peptide fragment from the C-terminal juxtamembrane region autonomously inhibits adenylyl cyclase activity in a neuroblastoma membrane preparation. The cannabinoid receptor antagonist, SR141716A, failed to block the response. The peptide was able to evoke the response in membranes from Chinese hamster ovary (CHO) cells that do not express the CB1 receptor. These studies are consistent with a direct activation of Gi by the peptide. To test the importance of a BXBXXB sequence, Lys403 was acetylated, resulting in a peptide having similar affinity but reduced efficacy. N-Terminal truncation of Arg401 resulted in a 6-fold loss of affinity, which was not further reduced by sequential truncation of up to the first seven amino acids, four of which are charged. N-Terminal-truncated peptides exhibited maximal activity, suggesting that Gi activation can be conferred by the remaining amino acids. Truncation of the C-terminal Glu417 or substitution of Glu417 by a Leu or of Arg401 by a Norleucine reduced activity at 100 microM. The C-terminal juxtamembrane peptide was constrained to a loop peptide by placement of Cys residues at both terminals and disulfide coupling. This modification reduced the affinity 3-fold but yielded near-maximal efficacy. Blocking the Cys termini resulted in a loss of efficacy. Circular dichroism spectropolarimetry revealed that all C-terminal juxtamembrane peptide analogues exist in a random coil conformation in an aqueous environment. A hydrophobic environment (trifluoroethanol) failed to induce alpha-helix formation in the C-terminal juxtamembrane peptide but did so in less active peptides. The anionic detergent sodium dodecyl sulfate induced alpha-helix formation in all analogues except the loop peptide, where it induces a left-handed PII conformation. It is concluded that alpha-helix formation is not required for Gi activation.
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PMID:Regulation of Gi by the CB1 cannabinoid receptor C-terminal juxtamembrane region: structural requirements determined by peptide analysis. 1007 92

The two inbred strains of mice C57BL/6 and DBA/2 mice have been shown to differ significantly in their preference for alcohol (EtOH). These strains of mice have been employed to study various aspects of pharmacological and behavioral effects of EtOH. We have previously demonstrated that chronic EtOH exposure down-regulated cannabinoid receptors (CB1) in mouse synaptic plasma membranes and enhanced the synthesis of endogenous cannabimimetic compound anandamide (AnNH) in human neuroblastoma cells. The purpose of the present study was to investigate whether there were differences in the density and the affinity of CB1 receptors in the brains of the two inbred C57BL/6 (alcohol-preferring) and DBA/2 (alcohol avoiding) mice. The results indicate the presence of specific CB1 receptors in the brain membranes of both the strains. It was also found that the CB1 receptor densities (B(max)) were 25% lower in C57BL/6 (0.66 +/- 0.15 pmol/mg protein) compared with that of DBA/2 (0.88 +/- 0.08 pmol/mg protein) mice. Significant differences in the affinity were also observed between the two lines (K(d), 0.68 +/- 0.15 nM for C57BL/6 and 2.21 +/- 0.56 nM for DBA/2). The competition studies with SR141716A, a CB1 receptor antagonist, and 2-arachidonylglycerol (2-AG) and anandamide (AnNH), known CB1 receptor agonists, all showed a substantial decrease in [(3)H]CP-55,940 binding in both strains of mice with a higher K(i) values in the DBA/2 mice. These results suggest that CB1 receptor signal transduction may play an important role in controlling the voluntary EtOH consumption by these strains of mice.
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PMID:Distinct differences in the cannabinoid receptor binding in the brain of C57BL/6 and DBA/2 mice, selected for their differences in voluntary ethanol consumption. 1072 75

1. Opioid (mu, delta, kappa) and cannabinoid (CB1, CB2) receptors are coupled mainly to Gi/Go GTP-binding proteins. The goal of the present study was to determine whether different subtypes of opioid and cannabinoid receptors, when coexpressed in the same cell, share a common reservoir, or utilize different pools, of G proteins. 2. The stimulation of [35S]GTPgammaS binding by selective opioid and cannabinoid agonists was tested in transiently transfected COS-7 cells, as well as in neuroblastoma cell lines. In COS-7 cells, cotransfection of mu- and delta-opioid receptors led to stimulation of [35S]GTPgammaS binding by either mu-selective (DAMGO) or delta-selective (DPDPE) agonists. The combined effect of the two agonists was similar to the effect of either DAMGO or DPDPE alone, suggesting the activation of a common G-protein reservoir by the two receptor subtypes. 3. The same phenomenon was observed when COS-7 cells were cotransfected with CB1 cannabinoid receptors and either mu- or delta-opioid receptors. 4. On the other hand, in N18TG2 neuroblastoma cells, which endogenously coexpress CB1 and delta-opioid receptors, as well as in SK-N-SH neuroblastoma cells, which coexpress mu- and delta-opioid receptors, the combined effects of the various agonists (the selective cannabinoid DALN and the selective opioids DPDPE and DAMGO) were additive, implying the activation of different pools of G proteins by each receptor subtype. 5. These results suggest a fundamental difference between native and artificially transfected cells regarding the compartmentalization of receptors and GTP-binding proteins.
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PMID:Opioid and cannabinoid receptors share a common pool of GTP-binding proteins in cotransfected cells, but not in cells which endogenously coexpress the receptors. 1078 29

The CB1 cannabinoid receptor in N18TG2 neuroblastoma cells inhibits adenylate cyclase, and this response can be mimicked by a peptide corresponding to the juxtamembrane C-terminal domain (CB(1)401-417). Guanosine 5'-O-(3-thio)triphosphate binding to G proteins can be stimulated by both peptide CB(1)401-417 and peptides corresponding to the third intracellular loop [Howlett, A.C., Song, C., Berglund, B.A., Wilken, G.H. & Pigg, J.J. (1998) Mol. Pharmacol. 53, 504-510; Mukhopadhyay, S., Cowsik, S.M., Welsh, W.J. & Howlett, A.C. (1999) Biochemistry 38, 3447-3455]. In Chaps-solubilized N18TG2 membranes, the CB1 receptor coimmunoprecipitated with all three Gi subtypes. Pertussis toxin significantly reduced the CB(1) receptor-G alpha(i) association and attenuated the CB(1)401-417-induced inhibition of adenylate cyclase. CB(1)401-417 significantly reduced the CB(1) receptor association with G alpha(i3), but not with G alpha(i1) or G alpha(i2). In contrast, third intracellular loop peptides significantly reduced the CB(1) receptor association with G alpha(i1) and G alpha(i2), but not G alpha(i3). These interactions are specific for the CB(1) receptor because a peptide corresponding to the juxtamembrane C-terminal domain of the CB(2) receptor failed to compete for the association of the CB1 receptor with any of the Gi alpha subtypes, and was not able to activate Gi proteins to inhibit adenylate cyclase. These studies indicate that different domains of the CB(1) receptor direct the interaction with specific G protein subtypes.
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PMID:CB1 receptor-G protein association. Subtype selectivity is determined by distinct intracellular domains. 1116 87

The morphological remodeling of neuronal cells influences neurogenesis and brain functions. We hypothesize that psychoactive and neurotoxic effects of cannabinoids may be mediated, at least in part, by their morphoregulatory activities. In the present study, mouse neuroblastoma N1E-115 cells were used as an in vitro model to investigate cannabinoid-induced neurite remodeling effects and to identify the involvement of cannabinoid receptors in this neurite remodeling process. Using reverse transcription-polymerase chain reaction and immunofluorescence microscopy, the endogenously expressed CB1, but not CB2, cannabinoid receptors were detected in morphologically differentiated N1E-115 cells. Activation of these natively expressed CB1 cannabinoid receptors by cannabinoid agonist HU-210 led to a concentration-dependent inhibition of adenylate cyclase activity. Importantly, HU-210 treatment induced neurite retraction in a concentration-dependent manner. Pretreatment of N1E-115 cells with a CB1 antisense oligodeoxynucleotide (ODN) suppressed HU-210-induced inhibition of forskolin-stimulated cAMP accumulation, indicating that the knocking down of functional CB1 cannabinoid receptor expression was achieved. Antisense ODN pretreatment also abolished HU-210-induced neurite retraction, demonstrating the involvement of CB1 cannabinoid receptors in mediating the neurite remodeling effects of HU-210. In addition, reversing HU-210-induced intracellular cAMP declination by 8-Br-cAMP partially prevented HU-210-induced neurite retraction, indicating the involvement of cAMP-dependent signaling pathways in mediating the neurite remodeling function of CB1 cannabinoid receptors in N1E-115 cells. These data demonstrate that neurite remodeling is a newly discovered function of CB1 cannabinoid receptors. This morphoregulatory function of CB1 cannabinoid receptors might be a new mechanism that mediates the psychoactive and neurotoxic effects of cannabinoids in developing and adult brain.
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PMID:CB1 cannabinoid receptor-mediated neurite remodeling in mouse neuroblastoma N1E-115 cells. 1149 71

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