Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The mechanisms of action of two different serotonin receptors, found in a neuronal cell line (neuroblastoma X glioma hybrid cells) and in a non-excitable glioma cell line, were explored. In both cell lines, serotonin induced a dose-dependent, transient rise of cytosolic Ca2+ activity (measured by fura-2 or indo-1 fluorescence). Ca2+ channel blockers (Ni2+ and La3+, not nifedipine) suppressed the Ca2+ response to serotonin in the hybrid cells but not in the glioma cells. After application of Ca2+ ionophores (ionomycin and A23187) in order to short-circuit internal Ca2+ stores, serotonin was still able to induce a Ca2+ response in the hybrid cells but not in the glioma cells. Serotonin dose-dependently stimulated the rate of 45Ca2+ uptake several-fold in the hybrid cells, but hardly at all in the glioma cells. Thus, in the neuronal cell line cytosolic Ca2+ activity is raised through enhancement of Ca2+ entry into the cells from the extracellular environment via 5-HT3 receptors (blocked by ICS 205-930, MDL 72222 and GR 38032 F). The depolarization response caused by serotonin in the hybrid cells is due to activation of cation conductance(s), obviously allowing entry of extracellular Ca2+. In contrast to the neuronal cell line, in the glial cell line the rise of Ca2+ activity is mediated by ketanserin-susceptible 5-HT2 receptors (not affected by treatment with pertussis toxin) mainly liberating Ca2+ from internal stores. In the glioma cells the release of Ca2+ from internal stores leads to opening of Ca2+-dependent K+ channels, responsible for the hyperpolarizing response. Thus, the neuronal and the glial cell lines might provide suitable systems in which to study the diverse cellular functions triggered by the rise of cytosolic Ca2+ activity, which is caused by different serotonin receptors.
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PMID:Serotonin regulates cytosolic Ca2+ activity and membrane potential in a neuronal and in a glial cell line via 5-HT3 and 5-HT2 receptors by different mechanisms. 260 42

A neuroblastoma X Chinese hamster embryonic brain explant hybrid cell line (NCB-20) expressed 5-hydroxytryptamine (5-HT1) receptors, linked to adenylate cyclase, which closely resembled 5-HT1 receptors previously characterized in central nervous tissue. However, the affinity of the receptors for 5-HT was only 150 nM compared to 5 nM in membranes prepared from cerebral cortex. The elevation of cyclic AMP levels in NCB-20 cells produced by 5-HT was found additive to that produced by cholera toxin but synergistic with that produced by either prostaglandin E1 (PGE1) or forskolin, suggesting that these latter two agents elevate cyclic AMP levels by a different mechanism than 5-HT. The elevation of cyclic AMP levels by either 5-HT or PGE1 was reversed by [D-Ala2,D-Leu5]enkephalin (DADLE), morphine, clonidine, and 3,4-dihydroxyphenylethylamine (dopamine) on a short (30 min) time scale. However, continued exposure to DADLE resulted in loss of the initial inhibitory effects of DADLE after 6 h and return of cyclic AMP levels to that seen with either 5-HT or PGE1 alone. When the DADLE exposure time was increased to 48 h, 5-HT produced a further twofold increase in cyclic AMP levels, but there was no increase in the responsiveness of the cells to PGE1 unless naloxone was added 1 h prior to treatment with PGE1. Scatchard analysis showed that the increased potency of 5-HT resulted from an increase in receptor affinity for 5-HT (from a KD of 150 +/- 20 nM to one of 20 +/- 7 nM), with a reduction in the number of apparent binding sites. The 5-HT supersensitivity observed in NCB-20 cells may be a good model for neurotransmitter interactions that produce desensitization or facilitation in the intact nervous system.
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PMID:Evidence for [D-Ala2,D-Leu5]enkephalin-induced supersensitivity to 5-hydroxytryptamine in a neurotumor x brain hybrid cell line (NCB-20). 299 93

[3H]ICS 205-930 recognition sites were analyzed in membranes prepared from murine neuroblastoma N1E-115 cells. [3H]ICS 205-930 bound rapidly, reversibly, and stereoselectively to a homogeneous population of high affinity recognition sites: Bmax = 40 +/- 5 fmol/mg of protein, pKD = 9.20 +/- 0.05 (n = 11). Nonlinear regression and Scatchard analysis of saturation data suggested the existence of a single class of [3H]ICS 205-930 recognition sites on N1E-115 cells. The affinity of [3H]ICS 205-930 determined in kinetic studies was in agreement with that obtained under equilibrium conditions. Competition studies carried out with a large variety of agonists and antagonists also suggested the presence of a homogeneous population of [3H]ICS 205-930 recognition sites. [3H]ICS 205-930-binding sites displayed the pharmacological profile of a 5-HT3 receptor. Potent 5-HT3 receptor antagonists showed nM affinities for [3H]ICS 205-930-binding sites with the following rank order of potency: SDZ 206-830 greater than SDZ 206-792 greater than ICS 205-930 greater than BRL 43694 greater than quipazine greater than BRL 24924 greater than MDL 72222 greater than GR 38032F. Methiothepine, mCPP, and metoclopramide showed sub-microM affinity. The rank order of potency of agonists was: 5-HT greater than phenylbiguanide = 2-methyl-5-HT much greater than 5-methoxytryptamine = 5-carboxamidotryptamine. All antagonist competition curves were steep (pseudo-Hill coefficients not lower than 1), monophasic, and best fit for a one-site model; 5-HT and 2-methyl-5-HT produced pseudo-Hill coefficients of 1.2-1.4. Drugs acting at 5-HT1, 5-HT2, alpha- and beta-adrenergic, dopaminergic, and histaminergic receptors (methysergide, ketanserin, propranolol, phentolamine, sulpiride, SCH 23390, cimetidine) were essentially inactive at 10 mumol/liter. The binding of [3H]ICS 205-930 was not affected by guanine and adenine nucleotides (GTP, GppNHp, and ATP) at 1 mmol/liter. These nucleotides did not affect the binding of agonists, suggesting that 5-HT3 recognition sites are not coupled to G-proteins. The interactions of agonists and antagonists with [3H]ICS 205-930 recognition sites were competitive in nature, as demonstrated by saturation experiments carried out with [3H]ICS 205-930 in the presence and the absence of unlabeled compounds: apparent Bmax values were not reduced, whereas apparent KD values were increased in the presence of competing ligands.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Identification of serotonin 5-HT3 recognition sites in membranes of N1E-115 neuroblastoma cells by radioligand binding. 335 95

The influence of memantine on several properties of a neuronal cell line was tested. The aim was to get some insight into possible mechanisms of action of this drug which is therapeutically applicable in treatment of spasticity, Parkinson's disease, and cerebral coma. In neuroblastoma X glioma hybrid cells, memantine, at micromolar concentrations, blocked the depolarization induced by iontophoretically applied serotonin (5-hydroxytryptamine, 5-HT). In the hybrid cells, receptors of the 5-HT3 type mediated the depolarization, which was frequently accompanied by a series of action potentials. The inhibition by memantine of the serotonin response occurred fast and was completely reversible, irrespective of whether the cell showed a stable membrane potential or spontaneous action potentials. However, memantine did not alter spontaneous or electrically evoked action potential activity in the hybrid cells, and apparently did not block the underlying ionic conductances. Furthermore memantine did not affect either the cation permeability activated by substance P in the hybrid cells or the K+ channel triggered by bradykinin in a glioma cell line. Thus, memantine appears specifically to suppress the ion channel opened by serotonin in the hybrid cells. The interaction of memantine with serotonin receptors and the associated ion channels reported here, might give an important clue, as to a site of action of memantine in the nervous system.
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PMID:Memantine (1-amino-3,5-dimethyladamantane) blocks the serotonin-induced depolarization response in a neuronal cell line. 335 74

Serotonin (5HT) and dopamine (DA) induce, in neuroblastoma N1E-115 cells, a transient membrane depolarization associated with an inward current. The half-maximum response is obtained with 2 microM 5HT or 200 microM DA. The maximum response to 5HT is 2-3 times that to DA. The selective 5HT3 receptor antagonists ICS 205-930 and MDL 72222 at nanomolar concentrations block both the 5HT- and the DA-induced response. High concentrations (10 microM) of 5HT2 receptor antagonists are without effect. It is concluded that, in N1E-115 cells, 5HT and DA activate a single population of 5HT3 receptors.
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PMID:The dopamine response in mouse neuroblastoma cells is mediated by serotonin 5HT3 receptors. 375 83

NCB-20 cells (neuroblastoma X fetal Chinese hamster brain hybrids) are equipped with a [3H]5-hydroxytryptamine [( 3H]5-HT) uptake system and [3H]imipramine recognition sites. Approximately 80% of the radioactivity taken up by cells incubated with [3H]5-HT was identified with 5-HT. [3H]5-HT uptake was temperature-dependent, partially sodium-dependent, saturable (Km = 7.3 +/- 0.6 microM; Vmax = 2.0 +/- 0.6 pmol/min/mg), and inhibited by clomipramine, imipramine, fluoxetine, and desipramine, but not by iprindole, mianserin, or opipramol. Lineweaver-Burk plots showed a competitive type of inhibition by imipramine and fluoxetine. [3H]5-HT uptake was not inhibited by nisoxetine or benztropine. [3H]Imipramine binding sites had a KD of 12 +/- 2 nM and a Bmax of 22 +/- 7 pmol/mg protein. The binding was sodium-sensitive although to a lesser extent than that found with brain membranes. Imipramine binding was displaced by tricyclic antidepressants with the following order of potency: clomipramine greater than imipramine greater than fluoxetine greater than desipramine much greater than iprindole = mianserin greater than opipramol. These results suggest that imipramine binding sites are present together with the 5-HT uptake sites in NCB-20 cells and that these sites interact functionally but are different biochemically.
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PMID:5-Hydroxytryptamine uptake and imipramine binding sites in neurotumor NCB-20 cells. 387 88

The major mechanism by which the serotonin neurotoxin 5,6-dihydroxytryptamine (5,6-DHT) expresses its neurodegenerative action may involve alkylation of biological nucleophiles by the electrophilic quinoid autoxidation products. To determine the relative importance of various sites on these autoxidation products toward alkylation we have rationally designed and synthesized 4-Me-5,6-DHT (16a), 7-Me-5,6-DHT (16b), and 4,7-Me2-5,6-DHT (16c). The indole nucleus of these analogues was constructed by the reductive cyclization of the corresponding 2, beta-dinitrostyrenes, and the aminoethyl side chain was introduced via gramine methiodides. Redox data showed that all the analogues are more readily oxidized compared to 5,6-DHT. The biological activity was evaluated in differentiated neuroblastoma N-2a cells in culture. The order of inhibitory potency, as determined by measuring the inhibition of incorporation of [3H]thymidine into DNA, was 16c much greater than 16a greater than 5,6-DHT approximately equal to 16b. The order of affinity (expressed as IC50 values in microM) for serotonergic uptake as determined by measuring their inhibition of [3H]-5-HT uptake was 5,6-DHT (4) greater than 16c (20) greater than 16a (23) greater than 16b (52). The results of these studies established that these rationally designed C-methylated analogues of 5,6-DHT are suitable probes for elucidating the molecular mechanism of action of 5,6-DHT.
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PMID:Molecular mechanism of action of 5,6-dihydroxytryptamine. Synthesis and biological evaluation of 4-methyl-, 7-methyl-, and 4,7-dimethyl-5,6-dihydroxytryptamines. 403 30

Synthesis, localization and release of serotonin (5-HT) were studied in cholinergic neuroblastoma X glioma NG108-15 cells. The content of 5-HT and tryptophan hydroxylase activity rose substantially when hybrid cells were differentiated by prostaglandin E1 plus theophylline, or dibutyryl cAMP. Localization of [3H]5-HT taken up into differentiated NG108-15 cells was examined by electron microscopic radioautography. Silver grains were observed mostly in neurites, indicating that neurites of differentiated NG108-15 cells are the preferential uptake site of [3H]5-HT. Statistical analysis of the results of electron microscopic radioautographs revealed that silver grains had a high affinity for dense core vesicles of 60-170 nm diameter, though grains were also located over endoplasmic reticulum, mitochondria and cytosol. Dense core vesicles were abundant in neurites, and less numerous in cell bodies of the hybrid cells. [3H]5-HT taken up into NG108-15 cells was released by potassium stimulation in the presence of Ca2+. The results indicate that NG108-15 hybrid cells manifest many properties comparable to those of serotonergic neurons.
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PMID:Localization of [3H]serotonin in neuroblastoma x glioma hybrid cells. 408 12

Benzodiazepines have been shown to change the turnover rate of 5-HT, ACh and catecholamines stored in selected brain areas, but the doses required for these effects are several-fold higher than those which elicit a persistent punished behavior or antagonize isoniazid, bicuculline or picrotoxin convulsion. The selective antagonism against convulsions elicited by drugs that impair GABAergic transmission, the capability of muscimol and other GABA receptors agonists to mimic behavioral and anticonvulsant action of the benzodiazepines have suggested that benzodiazepines facilitate GABA transmission. This facilitation of the GABA tranmission is due to an allosteric facilitation of high-affinity GABA binding to postsynaptic receptors. Also, the high-affinity binding of the benzodiazepines can be facilitated by GABA mimetics. Endogenous inhibitors of the benzodiazepines and GABA binding extracted from synaptic membranes play a role in facilitating these interactions. Using neuroblastoma 2A cells as a model and Cl- influx as an index of GABA receptor activation, it will be shown that the benzodiazepines facilitates not only GABA binding but also its action on Cl- channels. Also, glioma C6 cells have high affinity receptors for GABA and benzodiazepine binding but these binding sites are not linked to a Cl- channel. It is concluded that the benzodiazepines displace a regulatory protein for high-affinity GABA receptors and thereby facilitate GABAergic transmission.
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PMID:Benzodiazepines and neurotransmitters. 610 85

Serotonin has been previously shown to stimulate palate reorientation. To elucidate the mechanism by which the neurotransmitter may be regulating palate morphogenesis, the effects of serotonin on cell motility and various metabolic reactions have been measured in vitro. To monitor cell motility, a chemotactic system was employed in which cultured palate mesenchymal cells in a modified Boyden chamber migrate toward the chemoattractant(s) in N-18 neuroblastoma conditioned medium. Serotonin stimulated cell motility and 10(-5) M was optimal with nearly 100% stimulation achieved. With N-18 conditioned medium diluted 1:100, serotonin stimulated cell motility 4.9-fold. Serotonin itself was not chemotactic but modulated cell movement in the presence of the chemoattractant. Protein carboxyl methylation was stimulated by serotonin about 100% at concentrations ranging from 3 X 10(-7) M to 3 X 10(-6) M in different experiments. The net stimulation may have been elicited by an indirect effect since serotonin also inhibited demethylation of protein methyl esters. Serotonin was shown to inhibit cyclic AMP in cultured palate cells: 10(-5) M agonist depressed levels to 19% of control in 3 h. Further, prostaglandin E1, which stimulated cyclic AMP levels, markedly inhibited cell motility in the chemotactic assay. Thus there is an inverse relationship between cyclic AMP levels and cell motility in fetal palate cells. Finally it was observed that serotonin stimulated cyclic GMP levels; 10(-5) M serotonin optimally stimulated cyclic GMP with a spike of stimulation (6.1-fold) within 30 sec. In summary, serotonin in palate cells stimulates both protein carboxyl methylation and cyclic GMP. Modulation of these reactions could be regulating cell motility and/or protein secretion, which in turn could function in palate reorientation.
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PMID:Serotonin regulation of palatal cell motility and metabolism. 631 57


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