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)

Whilst many human neuroblastoma cell lines have been studied to see if they are capable of taking up mIBG, few appear to have this ability. This contrasts markedly to the situation in vivo, where uptake has been demonstrated in the majority of tumours investigated. Here we report on the human neuroblastoma cell line SK-N-BE(2C) and demonstrate that mIBG uptake can occur in this cell line through 2 mechanisms. At low concentrations of mIBG (approximately 10(-8) M) an active transport process predominates, whereas at non-physiological levels (10(-4) M) uptake occurs through passive diffusion. The active transport process is ATP-, Na(+)- and temperature-dependent. Uptake is blocked by 10(-6) M desipramine, an inhibitor of the uptake-I mechanism involved in amine transport. In contrast, desipramine has no effect on the passive diffusion of mIBG into cells. The active transport mechanism for mIBG uptake appears rather promiscuous for biogenic amines, as dopamine, tyramine and nor-adrenaline were highly efficient at blocking mIBG entry to the cell. Serotonin and histamine were capable of interfering with mIBG uptake only at much higher concentrations. Electron microscopy of SK-N-BE(2C) cells revealed a paucity of neurosecretory granules. Biochemical investigations demonstrated the majority of mIBG to be present in the cytoplasm of cells. The availability of a human neuroblastoma cell line that grows well, both as xenograft and in culture, should further our understanding of the cytotoxic effects of mIBG and thus enhance its clinical usefulness.
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PMID:Meta-iodobenzylguanidine (mIBG) uptake and storage in the human neuroblastoma cell line SK-N-BE(2C). 198 65

The 5,6-dihydroxytryptamine (5,6-DHT) derivatives 4-fluoro- and 7-fluoro-5,6-DHTs (26a,b) and 4,7-difluoro-5,6-DHT (26c) were synthesized from 3-fluoroanisole (1) and 1,4-difluoro-2,3-dimethoxybenzene (13), respectively. Efficient methods were developed for the conversion of 1 to 4-fluoro- and 7-fluoro-5,6-bis(benzyloxy)indoles (12a,b, respectively), and 13 to 4,7-difluoro-5,6-[( diphenylmethylene)dioxy]indole (19) via reductive cyclization of 2-nitro-beta-(dialkylamino)styrenes prepared in situ from 2-nitrotoluenes. Indoles 12a,b and 19 were then converted to 26a-c via the corresponding indole-3-acetonitriles. The fluorine-substituted 5,6-DHTs displayed increased phenol acidities, determined spectrophotometrically, and decreased inherent potential to undergo oxidation as determined by cyclic voltammetry. Fluorine substitution did not have a significant adverse effect on the cytotoxic potential as judged from the IC50 values of 117, 125, 135, and 92 microM for 26a,c and 5,6-DHT, respectively, for the inhibition of incorporation of [3H]thymidine into the DNA of neuroblastoma clone N-2a cells in culture. Surprisingly, 26a-c exhibited 32-, 23-, and 13-fold higher affinities, respectively, compared to 5,6-DHT for the serotonergic uptake system of N-2a cells as measured by the ability of 26a-c and 5,6-DHT to antagonize the uptake of [3H]5-HT into the N-2a cells. These desirable chemical and biological properties of 26a-c should make them useful tools for the study of the molecular mechanism of neurodegenerative action of 5,6-DHT.
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PMID:Synthesis and biological evaluation of 4-fluoro-, 7-fluoro-, and 4,7-difluoro-5,6-dihydroxytryptamines. 210 Sep 97

5-Hydroxytryptamine (serotonin, 5-HT) stimulates basal adenylyl cyclase activity in membranes from guinea pig or rat hippocampi, but 5-HT inhibits forskolin-stimulated adenylyl cyclase activity in these same membranes. The opposing effects of 5-HT on adenylyl cyclase activity indicate that distinct 5-HT receptors, positively and negatively coupled to adenylyl cyclase, are present in these membranes. Stimulation of adenylyl cyclase activity is mediated by two distinct 5-HT receptors. The receptor with lower affinity for 5-HT, designated as RL, is apparently homologous with a 5-HT receptor present in rat collicular membranes, but it is not homologous with the stimulatory receptor characterized in neuroblastoma hybrid cell (NCB-20) membranes. The receptor with higher affinity for 5-HT is homologous with the 5-HT1A binding site. The magnitude of stimulation by 5-HT1A receptors is variable with respect to stimulation by RL and is sometimes completely absent. Inhibition of forskolin-stimulated adenylyl cyclase activity, in membranes from either rat or guinea pig hippocampus or rat cortex, is a functional correlate of the 5-HT1A binding site. This inhibitory response was used to determine the pharmacological characteristics of drugs that reportedly have high affinity for 5-HT1A binding sites, such as 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (PAPP) and (-)pindolol. PAPP inhibited adenylyl cyclase activity in guinea pig hippocampal membranes with an EC50 value of 27 +/- 3 nM. (-)Pindolol was a partial agonist in inhibiting adenylyl cyclase activity in guinea pig and rat hippocampal membranes. Because of the low intrinsic activity of (-)pindolol, it was tested as an antagonist of the inhibition produced by 5-HT1A receptor agonists in rat hippocampal membranes. The Kb of (-)pindolol was 40 nM as measured by a Schild plot. (-)Propranolol was a simple competitive antagonist at the rat hippocampal receptor with a Kb value of 550 nM. In summary, guinea pig and rat hippocampal membranes possess two distinct populations of 5-HT receptors, a 5-HT receptor that mediates inhibition of adenylyl cyclase activity and is pharmacologically homologous with the 5-HT1A binding site, and a stimulatory receptor that appears to be homologous with the 5-HT receptor first characterized in infant rat collicular membranes.
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PMID:Stimulation and inhibition of adenylyl cyclase by distinct 5-hydroxytryptamine receptors. 222 10

Serotonin (5-hydroxytryptamine; 5-HT) and its analogs activate adenylate cyclase in membrane particles from neuroblastoma NCB.20 cells. Low concentrations of GTP (EC50 = 60 nM) were required for activation by serotonin. Guanosine 5'-O-(2-thiodiphosphate) inhibited serotonin-activated cyclase in these cells. The nonhydrolyzable GTP analogs guanosine 5'-O-(3-thiotriphosphate) (EC50 = 3 nM) and guanylyl-imidodiphosphate (EC50 = 100 nM) substituted for GTP in potentiating serotonin activation. Pretreatment of the cells with cholera toxin potentiated enzyme activation by serotonin, whereas pertussis toxin was found to have little effect, indicating the involvement of the alpha subunit of a stimulatory GTP-binding protein in enzyme activation. Homologous desensitization of the serotonin-stimulated adenylate cyclase was demonstrated in membranes prepared from intact cells pretreated with serotonin. Cell membrane particles that were desensitized to serotonin were still responsive to beta-adrenergic agonists and to prostaglandin E1. Evidence is presented indicating that serotonin stimulation of adenylate cyclase is mediated by receptors that are distinct from other positively coupled receptors (beta-adrenergic, histamine, and prostacyclin). Equilibrium binding analysis with [3H]serotonin, [3H]lysergic acid diethylamide, and [3H]dihydroergotamine suggested that the site density was below the level of detection of binding of these radioligands. The pharmacological characteristics of the serotonin-activated cyclases were analyzed in order to compare these serotonin receptors with the family of different receptor subtypes. Correlation analysis between the potencies of different agonists and antagonists at the cyclase in these cells and their reported relative potencies for different serotonin receptor subtypes showed no correlation with the 5-HT1A, 5HT1B, 5HT1D, 5-HT2, and 5-HT3 receptors. On the other hand, the analysis showed that the NCB.20 serotonin receptors are similar but not identical to the rat and pig brain 5-HT1C receptors and to the serotonin receptors coupled to adenylate cyclase in the trematodes Schistosoma mansoni and Fasciola hepatica. The results point to a novel serotonin receptor which has a low density in these cells.
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PMID:Serotonin receptor-mediated activation of adenylate cyclase in the neuroblastoma NCB.20: a novel 5-hydroxytryptamine receptor. 233 46

The influence of extracellular calcium and magnesium ion concentrations upon 5-HT3 receptor-gated membrane currents in murine N1E-115 neuroblastoma cells has been studied under voltage-clamp conditions. A decrease in the concentration of either Ca2+ or Mg2+ from their standard values of 1.0 and 2.0 mM respectively augmented both the amplitude and duration of the 5-HT-induced current, whereas elevating the concentration of either divalent cation produced the opposite effect. Such modulation did not involve a change in the reversal potential of the response.
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PMID:Divalent cations modulate 5-HT3 receptor-induced currents in N1E-115 neuroblastoma cells. 246 26

Both substance P and, to a lesser degree, serotonin activate cation permeability in neuroblastoma x glioma hybrid cells, as determined by measurement of [14C]guanidinium uptake. Serotonin potentiates the action of substance P by shifting the concentration-effect curve of substance P to the left. The EC50 value for the synergistic effect of serotonin was around 0.3 microM. Dopamine and noradrenaline displayed comparable activity, albeit only at 50 and 130 times higher concentrations, respectively. The order of potency of various substance P-analogues was not changed by serotonin, indicating that the specificity of the substance P site on the hybrid cells was not affected by serotonin. Various other neurotransmitters and peptides had no effect on the response of the hybrid cells to substance P. The serotonin receptor interacting with the substance P receptor may be classified as a 5-HT3-receptor since methysergide, cimetidine, and ketanserin were ineffective, but two inhibitors specific for 5-HT3-receptors, ICS 205-930 (3 alpha-tropanyl-1H-indole-3-carboxylic acid ester) and MDL 72222 (1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate), blocked the effect of serotonin at nanomolar concentrations. However, the two serotonin antagonists might also be blocking the ion permeability, since at higher concentrations they fully inhibited the stimulation of guanidinium uptake by substance P or by substance P plus serotonin. The synergism between substance P and serotonin on the hybrid cells offers the opportunity to study the mechanism of interaction of neurotransmitter receptors on a permanent neuronal cell line.
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PMID:Substance P and serotonin act synergistically to activate a cation permeability in a neuronal cell line. 246 36

1. The neuroblastoma x glioma hybrid NG108-15 cell line has been widely studied as a neuronal model for its serotonergic, cholinergic, and peptidergic properties. 2. The catecholamine and serotonin content and that of their major metabolites have been determined by high-performance liquid chromatography with electrochemical detection (HPLC-EC) in NG108-15 cells under differentiated and undifferentiated conditions. 3. Cellular contents of L-DOPA, norepinephrine, (NE), L-epinephrine (EPI), and dopamine (DA) in differentiated cells, induced by 1 mM dibutyryl cyclic AMP (dBcAMP), are 149, 40, 129, and 124%, respectively, higher than those in undifferentiated cells. 4. 3,4-Dihydroxyphenethylacetic acid (DOPAC), the major metabolite of DA, is detectable only in differentiated cells. Similarly, DOPAC is present only in culture medium from differentiated cells, and not that of undifferentiated cells. 5. Serotonin (5-HT) is detectable only in undifferentiated cells; and the level of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-HT, is also 12.7% higher is undifferentiated cells. 6. Comparative analyses of differentiated and undifferentiated cells in monolayer cultures and undifferentiated cells cultured in the presence of 1 mM dBcAMP under suspension conditions suggest that change in the indolamine content is due to cellular changes upon morphological differentiation. 7. The clonal NG108-15 cell line is also catecholaminergic, in addition to cholinergic and serotonergic; and a shift of neurotransmitter pattern from serotonin to dopamine production occurs during morphological differentiation.
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PMID:Modification of the indolamine content in neuroblastoma x glioma hybrid NG108-15 cells upon induced differentiation. 248 34

1. Ionic currents mediated by serotonin 5-HT3 receptors were studied in the mouse neuroblastoma cell line N1E-115, using suction pipettes for intracellular perfusion and voltage clamp recording. The dependence of the kinetics of the membrane current on serotonin concentration was investigated. 2. At a holding potential of -70 mV application of 5-HT (5-hydroxytryptamine creatinine sulphate) causes a transient inward current. The i-V curve of the peak amplitude is linear between -80 and 60 mV. The reversal potential is 20 +/- 4 mV (mean +/- S.D.). The kinetics of the transient ionic current are independent of the holding potential. 3. In the presence of 5-HT the membrane current decays to a small steady-state level with a single-exponential time course. The time constant of decay decreases with increasing concentration of the agonist, to a minimum value of 6.5 +/- 1.5 s for concentrations of 5-HT greater than or equal to 3 microM. 4. When the agonist is rapidly removed, single-exponential decay of the ionic current is observed. The time constant of this decay in the absence of 5-HT amounts to 6.9 +/- 1.5 s and is independent of the membrane potential and of the concentration of 5-HT used. 5. In the presence of low concentrations of 5-HT the peak amplitude of the inward current evoked with a high concentration of agonist is gradually reduced. The onset of this desensitization follows the same time course as the decay of the membrane current. In the range from 0.7 to 1.5 microM-5-HT both kinetic processes show the same steep concentration dependence. 6. Recovery from desensitization, measured at variable intervals after removal of the agonist, can be fitted by a single-exponential function with a time constant of 18 +/- 4 s. 7. The results show that the kinetic properties of the 5-HT3 receptor-mediated ionic current can only be described by a complex, co-operative model.
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PMID:Kinetics of the membrane current mediated by serotonin 5-HT3 receptors in cultured mouse neuroblastoma cells. 248 54

Serotonin (5-HT) induced a transient rise of the cyclic GMP level in neuroblastoma X glioma hybrid cells, half-maximally at 1 microM 5-HT. 2-Methyl-5-HT displayed an about 5 times lower potency but equal efficacy. alpha-Methyl-5-HT and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were completely ineffective at concentrations up to 30 microM. Antagonists specific for 5-HT3 receptors, ICS 205-930, GR 38032 F and MDL 72222, blocked the response to 5-HT at nanomolar concentrations but antagonists directed towards 5-HT1 and 5-HT2 receptors, ketanserin and methysergide, had no effect at concentrations up to 1 microM. Thus, 5-HT3 receptors are responsible for activating guanylate cyclase in the hybrid cells.
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PMID:Serotonin raises the cyclic GMP level in a neuronal cell line via 5-HT3 receptors. 254 82

Serotonin (5-HT) evoked a rise of cytosolic Ca2+ activity in neuroblastoma X glioma hybrid cells, most probably due to the entry of extracellular Ca2+; cyclic GMP synthesis was also stimulated. The rise of both cytosolic Ca2+ activity and of cyclic GMP level was blocked by memantine (1-amino-3,5-dimethyladamantane). Memantine inhibited the rise of the cyclic GMP level non-competitively (Ki about 50 microM). Thus, memantine suppresses the effects of 5-HT in the neuronal cell line, most likely by blocking Ca2+-permeable ion channels. This interpretation is in line with the previously reported finding that memantine suppressed the 5-HT-induced depolarizing response in the same cell line.
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PMID:Memantine inhibits serotonin-induced rise of cytosolic Ca2+ activity and of cyclic GMP level in a neuronal cell line. 254 83


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