Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies indicate that ethanol (EtOH) potentiates ion current through the channel associated with the 5-hydroxytryptamine3 (5-HT3)-type serotonin receptor. The present study was designed to determine 1) whether such potentiation occurs in adult mammalian neurons expressing 5-HT3 receptors; 2) whether potentiation is selective for the 5-HT3 receptor, relative to other ligand-gated ion channels; and 3) possible mechanisms by which EtOH potentiates this response. EtOH potentiated 5-HT3 receptor-mediated ion current in freshly isolated nodose ganglion neurons at concentrations similar to those previously reported to be effective in neuroblastoma cells (25-100 mM). Current was blocked by the selective 5-HT3 antagonist ICS 205-930 even in the presence of EtOH, and current activated by a 5-HT3 agonist (2-methyl-5-HT) was potentiated by EtOH. Thus, EtOH appears to produce potentiation via an alteration in the function of 5-HT3 receptors and not through an independent effect. gamma-Aminobutyric acidA receptor-mediated Cl- current was not potentiated by EtOH in neurons in which potentiation of responses to 5-HT was observed. Methanol potentiated 5-HT3 receptor-mediated current with a potency lower than that of EtOH. Potentiation by EtOH decreased with increasing 5-HT concentration. In addition, EtOH increased the decay rate of current. EtOH did not alter the reversal potential of the 5-HT3 receptor-mediated current. These observations indicate that intoxicating concentrations of EtOH selectively potentiate 5-HT3 receptor-mediated responses by increasing the apparent potency of 5-HT for activating ion current.
Mol Pharmacol 1991 Aug
PMID:Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons. 171 16

In this study the similarities and differences between the M2 and M4 subtypes in their recognition of agonists were explored. A CHO-K1 cell line transfected with the human m2 receptor was used as a homogeneous M2 tissue for comparison with two putative M4 systems (rat striatum and the N1E-115 mouse neuroblastoma cell line). The equilibrium binding dissociation constants and intrinsic efficacies for seven muscarinic agonists were determined for their stimulation of cyclic AMP inhibition via the M2 and M4 receptors. Partial receptor occlusion with propylbenzilylcholine mustard was used to determine binding constants for the more efficacious drugs and the reference agonist oxotremorine-M. The binding dissociation constants and relative efficacies for other agonists were then determined in reference to oxotremorine-M by a null method. For the M2 receptor the agonist binding dissociation constants ranged in potency from oxotremorine (1.5 microM) to bethanechol (171 microM), whereas relative efficacies varied from that of muscarine (relative efficacy = 0.9) to the value for McN-A343 (relative efficacy = 0.04). In general, most agonists bound with similar potencies to M2 and M4 receptors (Kd values within a factor of 2-3). However, oxotremorine bound to the N1E-115 and striatal M4 receptors about 3-fold and 10-fold less potently, respectively, than it did to the M2 receptor. Another exception was pilocarpine, which bound to the N1E-115 receptor (1.9 microM) with 8-fold and 12-fold higher potency than to the CHO-K1 M2 receptor and the striatal M4 receptor, respectively. Despite the low affinity of bethanechol for the M2 receptor, it was an efficacious agonist (maximal response equivalent to that of oxotremorine-M; relative efficacy = 0.6) at this subtype, whereas it was a partial agonist (60%) with lesser efficacy in the clonal M4 system. In contrast, McN-A343 and arecoline were significantly more efficacious at the two M4 receptors than they were at the M2 receptor. The M4 system in the rat striatum displayed some similarity to the N1E-115 M4 system, with regard to the efficacy ranking for certain agonists (arecoline greater than bethanechol greater than McN-A343 greater than or equal to pilocarpine). This rank order was different from the ranking of these four agonists in the M2 system, indicating that these two M4 receptors are more similar to each other in efficacy ranking than they are to the M2 receptor. However, the rat striatal and N1E-115 M4 receptor differed in their binding of oxotremorine and pilocarpine, indicating that these two M4 systems were not pharmacologically identical.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1991 Dec
PMID:Interactions of agonists with M2 and M4 muscarinic receptor subtypes mediating cyclic AMP inhibition. 172 2

1. The effects of gamma-interferon (gamma-IFN), retinoic acid (RA), and cytosine arabinoside (ARA-C) on the growth, morphology, and phenotype of the human neuroblastoma (NB) cell lines, LAN-1 and GI-ME-N, have been extensively tested. 2. RA, gamma-IFN, and ARA-C induced a dose-dependent morphological differentiation and growth inhibition, without affecting cell viability. Cells exposed to 10(-6) M RA or 1000 U/ml gamma-IFN significantly decreased their growth rate within the first 24 and 48 hr of culture, respectively. Cells became smaller and polygonal and sprouted long cellular processes with varicosities along their courses. In contrast, ARA-C-differentiated cells were larger and flattened, with few elongated dendritic processes. 3. Analysis of membrane and cytoskeletal markers by immunofluorescence and Western blot showed several changes in NB-specific antigen expression after 5 days of treatment with all inducing agents. Analysis of labeled phosphatidylinositol metabolites from prelabeled cells showed, within 1 min of treatment with RA, a rapid decrease in inositol 1,4,5-trisphosphate and of 1,2-diacylglycerol levels. No changes in inositol phospholipid metabolism were observed in gamma-IFN- or ARA-C-treated cells. 4. We conclude that RA-induced decrease in phosphatidylinositol (PI) hydrolysis is not likely to be a consequence of the acquisition of a different phenotype, as its changes precede the acquisition of neuronal markers. In addition, gamma-IFN and ARA-C, both inducing a mature phenotype, did not affect PI hydrolysis. 5. Decreased PI hydrolysis seems to be sufficient, although not necessary, to commit NB cells to neuronal differentiation. Analysis of molecular mechanisms associated with NB cell differentiation may be helpful to clarify the potential of various biological agents in affecting the development of the neural cell.
Cell Mol Neurobiol 1991 Aug
PMID:Gamma-interferon, retinoic acid, and cytosine arabinoside induce neuroblastoma differentiation by different mechanisms. 175 63

1. Dimethylsulfoxide-induced differentiated neuroblastoma express high levels of membrane 21 to 23-kDa carboxyl methylated proteins. Relationships among methylation, isoprenylation, and GTP binding in these proteins were investigated. Protein carboxyl methylation, protein isoprenylation, and [alpha-32P]GTP binding were determined in the electrophoretically separated proteins of cells labeled with the methylation precursor [methyl-3H]methionine or with an isoprenoid precursor [3H]mevalonate. 2. A broad band of GTP-binding proteins, which overlaps with the methylated 21 to 23-kDa proteins, was detected in [alpha-32P]GTP blot overlay assays. This band of proteins was separated in two-dimensional gels into nine methylated proteins, of which four bound GTP. 3. The carboxyl-methylated 21 to 23-kDa proteins incorporated [3H]mevalonate metabolites with characteristics of protein isoprenylation. The label was not removed by organic solvents or destroyed by hydroxylamine. Incorporation of radioactivity from [3H]mevalonate was enhanced when endogenous levels of mevalonate were reduced by lovastatin, an inhibitor of mevalonate synthesis. Lovastatin blocked methylation of the 21 to 23-kDa proteins as well (greater than 70%). 4. Methylthioadenosine, a methylation inhibitor, inhibited methylation of these proteins (greater than 80%) but did not affect their labeling by [3H]mevalonate. The results suggest that methylation of the 21 to 23-kDa proteins depends on, and is subsequent to, isoprenylation. The sequence of events may be similar to that known in ras proteins, i.e., carboxyl methylation of a C-terminal cysteine that is isoprenylated. 5. Lovastatin reduced the level of small GTP-binding proteins in the membranes and increased GTP binding in the cytosol. Methylthioadensoine blocked methylation without affecting GTP binding. 6. Thus, isoprenylation appears to precede methylation and to be important for membrane association, while methylation is not required for GTP binding or membrane association. The role of methylation remains to be determined but might be related to specific interactions of the small GTP-binding proteins with other proteins.
Cell Mol Neurobiol 1991 Aug
PMID:Relationship among methylation, isoprenylation, and GTP binding in 21- to 23-kDa proteins of neuroblastoma. 175 64

The toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its oxidized metabolite, and two recently synthesized 2'-alkyl derivatives of MPTP (methyl and ethyl), found to be more toxic in vivo in mice, have been compared in two neuroblastoma hybrid cell lines (NCB-20 and 140-3) that express the B form of monoamine oxidase (MAO), as tissue culture models for the mode of action of MPTP in the central nervous system. Unlike previously reported studies with cultured cells of neuronal origin expressing only MAO A, both of these cell lines were sensitive to MPTP. Consistent with the in vivo findings, the 2'-alkyl derivatives were much more toxic than MPTP and comparable to the oxidized metabolite MPP+ in their effects on cell survival and morphology. The cells could be protected against the reduced toxins, but not MPP+, by either the MAO A selective inhibitor, clorgyline or the MAO B selective inhibitor, deprenyl. The effectiveness of the MAO inhibitors in blocking the action of the reduced toxins was consistent with their ability to inhibit MAO activity in the cell cultures, but did not reflect MAO-substrate specificity of the toxins. Inhibitors of serotonin and dopamine uptake, which have been found to protect against MPTP toxicity in vivo, were generally ineffective in the cell cultures, with the exception of a marginal increase in survival of MPP(+)-treated 140-3 cells in the presence of the serotonin uptake inhibitor fluoxetine. These findings are discussed in relation to proposed in vivo mechanisms of MPTP cytotoxicity.
Mol Chem Neuropathol 1991 Oct
PMID:Toxicity of MPTP and structural analogs in clonal cell lines of neuronal origin expressing B type monoamine oxidase activity. 177 93

We have examined expression of the N-myc, c-fos and smg p25A genes in two human neuroblastoma cell lines during their differentiation. The decrease in the N-myc gene expression and the increase in the c-fos gene expression are observed during the differentiation of NB-1 cells into neuronal cells and of GOTO cells into Schwann-type cells. On the other hand, the smg p25A, a ras p21-like small GTP-binding protein, gene expression is increased in NB-1 cells but not in GOTO cells during their differentiation, suggesting that smg p25A is closely associated with the neuronal phenotype of neuroblastoma cells.
Brain Res Mol Brain Res 1991 Jan
PMID:Differential expression of the N-myc, c-fos, and smg p25A genes in human neuroblastoma cells during neuronal and Schwannian differentiation. 185 70

We analyzed the competition kinetics of quinuclidinyl benzilate (QNB) and QNB methiodide enantiomers on human NB-OK1 neuroblastoma (M1), rat cardiac (M2), and rat pancreas (M3) muscarinic binding sites. The association rate constants of the four drugs depended on the receptor subtype studied and were lower with pancreas (M3) (1-9 x 10(5) M-1 sec-1) than with cardiac (M2) (1-5 x 10(6) M-1 sec-1) and NB-OK1 (M1) (1-5 x 10(6) M-1 sec-1) binding sites. At each receptor subtype, we observed no significant difference between the association rate constants of the R- and S-enantiomers of either QNB or QNB methiodide. Receptor stereoselectivity, when present, was associated with differences in unlabeled drug dissociation rate constants. The dissociation rate constant varied much more than the association rate constant, when either (R)-QNB dissociation from the three subtypes (half-life, 77 min to greater than 340 min; best fit, 40 days) or dissociation of the four drugs from each receptor subtype (half-lives varying from 1.4 min to 4 hr at M1 receptors, 1.1 to 77 min at M2 receptors, and 3.5 min to greater than 340 min at M3 receptors were obtained by competition kinetics analysis) was compared.
Mol Pharmacol 1991 Sep
PMID:Binding kinetics of quinuclidinyl benzilate and methyl-quinuclidinyl benzilate enantiomers at neuronal (M1), cardiac (M2), and pancreatic (M3) muscarinic receptors. 189 27

The conversion of choline in cultures of the human neuroblastoma cell lines, LA-N-1 and LA-N-2 cells, was investigated in order to identify potential precursors in acetylcholine (AcCho) synthesis. LA-N-1, a catecholaminergic and LA-N-2, a cholinergic, cell line were incubated with [3H-methyl]choline (Cho) for varying periods of time up to 72 h. The radioactivity present in lipids and water-soluble metabolites increased linearly up to 24 h in both cell lines. Approximately 20% of the radioactivity associated with the water-soluble metabolites in both control (untreated) and retinoic acid-induced differentiated (RA-treated cells) LA-N-2 cells was present as Cho and AcCho. There was no detectable AcCho in the catecholaminergic cell line, LA-N-1. The untreated and RA-treated LA-N-1 and LA-N-2 cells were labeled for 24 h with [3H-methyl]Cho, followed by a chase in growth medium containing 100 microM unlabeled choline. The distribution of radioactivity in the LA-N-2 cells was 6-10% of AcCho, 84-89% as phosphocholine (PCho), 1-3% as glycerophosphocholine (GroPCho), and 2-4% as Cho. The distribution of radioactivity in the LA-N-1 cells was similar except for the absence of AcCho. The distribution of radioactivity in the culture medium of LA-N-1 cells was 70-80% as Cho, 20-30% as PCho, and 1-3% as GroPCho. In contrast, the radioactivity was equally distributed between Cho (50%) and PCho (50%), with only 1-3% as GroPCho in the medium of LA-N-2 cells.
Mol Chem Neuropathol 1991 Feb
PMID:The metabolic fate of [3H-methyl]choline in cultured human neuroblastoma cell lines, LA-N-1 and LA-N-2. 191 Mar 57

We have used cDNA subtractive cloning to identify a group of human genes that are expressed in diverse differentiated derivatives of neural crest origin but not in neuroblastoma cell lines. One of these genes was identified as CD44, which encodes an integral membrane glycoprotein that serves as the principal receptor for hyaluronate and participates in specific cell-cell and cell-extracellular matrix interactions. The repression of CD44 expression in neuroblastoma cell lines might be relevant to their high metastatic potential. We have cloned full-length cDNAs corresponding to CD44 trancscripts and identified a novel splice variant of CD44 lacking 31 amino acids of the extracellular domain. As a first step toward analysis of CD44 downregulation in neuroblastoma cells, we have mapped the CD44 RNA initiation site and analyzed the structure of the upstream regulatory region. We constructed a series of plasmids containing different amounts of CD44 upstream regulatory region linked to the bacterial chloramphenicol acetyltransferase gene and then analyzed their ability to promote transcription in neuroblastoma and melanoma cells. We found that a DNA segment including about 150 bp of the CD44 upstream region and the 5' end of the gene itself was sufficient to induce substantial transcription of the chloramphenicol acetyltransferase gene in both neuroblastoma and melanoma cells. Several upstream cis-acting elements contribute to the downregulation of CD44 in neuroblastoma cells, the most prominent being a 120-bp DNA fragment located 450 bp upstream to the RNA initiation site. Our data suggest that multiple factors might be involved in downregulation of CD44 in neuroblastoma cells.
Mol Cell Biol 1991 Nov
PMID:Expression of CD44 is repressed in neuroblastoma cells. 192 57

Angiotensin II (Ang-II) receptors were solubilized from differentiated N1E-115 neuroblastoma cell membranes with the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), whereas other detergents, such as digitonin, sodium cholate, and Triton X-100, were much less effective. Binding of 125I-Ang-II or the antagonist 125I-Sar1,Ile8-Ang-II to 1% CHAPS-solubilized membranes was saturable and of high affinity. Moreover, these solubilized receptors retained the pharmacological specificity characteristic of particulate receptors. Covalent cross-linking of 125I-Ang-II to either particulate or solubilized membrane fractions, with the homobifunctional cross-linker disuccinimidyl suberate, followed by size exclusion chromatography or sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, resulted in the identification of the same two distinct 125I-Ang-II binding entities, with approximate molecular masses of 111 kDa and 68 kDa. The estimated molecular weights of the Ang-II binding sites in differentiated N1E-115 cells are in good agreement with the molecular weights obtained previously from solubilized rat brain membranes, suggesting that the N1E-115 Ang-II receptors are similar to those present in the brain. Finally, solubilized N1E-115 membranes could be purified by Ang-II affinity chromatography, resulting in only a single protein (66 kDa), which retained its ability to specifically bind 125I-Ang-II.
Mol Pharmacol 1991 Nov
PMID:Biochemical analysis of solubilized angiotensin II receptors from murine neuroblastoma N1E-115 cells by covalent cross-linking and affinity purification. 194 41


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