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)

Vasoactive intestinal contractor (VIC) caused a series of biochemical events, including the temporal biphasic accumulation of 1,2-diacylglycerol (DAG), transient formation of Ins(1,4,5)P3, and increase in intracellular free Ca2+ [( Ca2+]i) in neuroblastoma NG108-15 cells. In these cellular responses, VIC was found to be much more potent in NG108-15 cells than in cultured rat vascular smooth-muscle cells. The single cell [Ca2+]i assay revealed that in the presence of nifedipine (1 microM) or EGTA (1 mM), the peak [Ca2+]i declined more rapidly to the resting level in VIC-stimulated NG108-15 cells, indicating that the receptor-mediated intracellular Ca2+ mobilization is followed by Ca2+ influx through the nifedipine-sensitive Ca2+ channel. Pretreatment with pertussis toxin only partially decreased Ins(1,4,5)P3 generation as well as the [Ca2+]i transient induced by VIC, whereas these events induced by endothelin-1 were not affected by the toxin, suggesting involvement of distinct GTP-binding proteins. The VIC-induced transient Ins(1,4,5)P3 formation coincident with the first early peak of DAG formation suggested that PtdIns(4,5)P2 is a principal source of the first DAG increase. Labelling studies with [3H]myristate, [14C]palmitate and [3H]choline indicated that in neuroblastoma cells phosphatidylcholine (PtdCho) was hydrolysed by a phospholipase C to cause the second sustained DAG increase. Down-regulation of protein kinase C (PKC) by prolonged pretreatment with phorbol ester markedly prevented the VIC-induced delayed DAG accumulation. Furthermore, chelation of intracellular CA2+ completely abolished the second sustained phase of DAG production. These findings suggest that PtdCho hydrolysis is responsible for the sustained production of DAG and is dependent on both Ca2+ and PKC.
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PMID:Receptor-linked early events induced by vasoactive intestinal contractor (VIC) on neuroblastoma and vascular smooth-muscle cells. 212 5

The hypothesis that the small portion of cellular phosphoinositide participating in signal transduction might be preferentially recycled within the plasma membrane was tested in rat glioma (C6) and murine neuroblastoma (N1E-115) cells. Percoll density gradient centrifugation was used to isolate a purified plasma membrane fraction and the subcellular distribution of all enzymes mediating phosphoinositide turnover was assessed. A small but significant proportion of PtdInsP2-specific phosphodiesterase was located in the plasma membrane but only two of the five enzymes required to replace PtdInsP2 (diacylglycerol kinase and PtdInsP kinase) also were present. CTP:phosphatidate cytidylyltransferase and CMP-phosphatidate:inositol phosphatidyltransferase were located exclusively in a microsomal fraction containing enriched levels of endoplasmic reticulum markers. Thus, diacylglycerol from agonist-stimulated cleavage of PtdInsP2, or phosphatidic acid formed from it, must be transferred to the endoplasmic reticulum for conversion to PtdIns. Plasma membrane also lacked PtdIns kinase. If the soluble PtdIns kinase has access to membrane-bound substrate, PtdIns may be phosphorylated to PtdInsP before or during transport to the plasma membrane. Phosphorylation by the predominantly plasma membrane PtdInsP kinase to form PtdInsP2 completes the cycle. PtdInsP phosphatase was present in all membrane fractions suggesting that PtdInsP can be returned to the PtdIns pool in plasma membrane and elsewhere. PtdInsP2 phosphatase was almost exclusively in the cytosol suggesting that reversible interchange between PtdInsP and PtdInsP2 in the plasma membrane may be modulated by the ability of this phosphatase to act on PtdInsP2 in the membrane. Thus, PtdIns resynthesis in the plasma membrane of these cells does not occur and is not required for phosphoinositide-mediated signal transduction.
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PMID:Phosphoinositide metabolism in cultured glioma and neuroblastoma cells: subcellular distribution of enzymes indicate incomplete turnover at the plasma membrane. 215 58

Hydrolysis of the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) produces two prospective intracellular messengers: inositol 1,4,5-trisphosphate (InsP3), which releases Ca2+ from intracellular stores; and diacylglycerol (DG), which activates protein kinase C. Here we show how the formation of these two substances triggered by one external messenger, bradykinin, leads to the appearance of two different sequential membrane conductance changes in the neurone-like NG108-15 neuroblastoma-glioma hybrid cell line. In these cells bradykinin rapidly hydrolyses PtdIns(4,5)P2 to InsP3 and DG, raises intracellular Ca2+ and hyperpolarizes then depolarizes the cell membrane. By voltage-clamp recording we show that the hyperpolarization results from the activation pharmacologically-identifiable species of Ca2+-dependent K+ current. This is also activated by intracellular injections of Ca2+ or InsP3 so may be attributed to the formation and action of InsP3. The subsequent depolarization results primarily from the inhibition of a different, voltage-dependent K+ current, the M-current that is also inhibited by DG activators. Hence we describe for the first time a dual, time-dependent role for these two intracellular messengers in the control of neuronal signalling by a peptide.
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PMID:Two polyphosphatidylinositide metabolites control two K+ currents in a neuronal cell. 242 90

In order to approach the molecular mechanism of Li+'s mood-stabilizing action, the effect of Li+ (LiCl) on inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] mass was investigated in human neuroblastoma SH-SY5Y cells, which express muscarinic M3 receptors, coupled to PtdIns hydrolysis. Stimulation of these cells, with the cholinergic agonist acetylcholine, resulted in a rapid and transient increase in Ins(1,4,5)P3 with a maximum at 10 s. This was followed by a rapid decline in Ins(1,4,5)P3 within 30 s to a plateau level above baseline, which gradually declined to reach a new steady state, which was significantly higher than resting Ins(1,4,5)P3 at 30 min. Li+ had no effect on Ins(1,4,5)P3 in resting cells, as well as on the acetylcholine-dependent peak of Ins(1,4,5)P3. However, Li+ caused a transient reduction (at 45 s), followed by a long lasting increase in the Ins(1,4,5)P3 (30 min), as compared with controls. The Li+ effects were dose-dependent and were observed at concentrations used in the treatment of bipolar disorders. Supplementation with inositol had no effect on the level of Ins(1,4,5)P3, at least over the time periods studied. Stimulation of muscarinic receptors with consequent activation of phospholipase C were necessary for the manifestation of Li+ effects in SH-SY5Y cells, Li+ did not interfere with degradation of Ins(1,4,5)P3 after receptor-blockade with atropine, suggesting that Li+ has no direct effect on the Ins(1,4,5)P3-metabolizing enzymes. A direct effect of Li+ on the phospholipase C also is unlikely. Blockade of Ca2+ entry into the cells by Ni2+, or incubation with EGTA, which reduces agonist-stimulated accumulation of Ins(1,4,5)P3, had no effect on the Li(+)-dependent increase in Ins(1,4,5)P3.
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PMID:Time-dependent effects of lithium on the agonist-stimulated accumulation of second messenger inositol 1,4,5-trisphosphate in SH-SY5Y human neuroblastoma cells. 757 58

Muscarinic stimulation of the human neuroblastoma cell line SK-N-BE(2) elicits hydrolysis of phosphoinositides and phosphatidylcholine (PtdCho) and produces a rapid and sustained elevation of diacylglycerol (DG) mass. PtdIns(4,5)P2 cleavage by phospholipase C (PLC) occurred immediately after carbachol (CCh) addition, and phosphoinositide hydrolysis was then sustained for at least 5 min. Cell stimulation, after extensive PtdCho labelling by long-term [3H]choline administration, resulted in an enhanced release of [3H]phosphocholine (PCho) into the external medium; enhanced [3H]PCho release, which occurred with a 15 s delay with respect to CCh addition, was particularly pronounced within the first minute of stimulation and proved to be caused by PtdCho-specific PLC activation. In fact, when cells were exposed to [3H]choline for a short period, to extensively label the intracellular PCho pool but not PtdCho, stimulation did not result in an enhanced release of [3H]PCho into the medium. PtdCho-specific phospholipase D (PLD) activation was documented by the accumulation of [3H]phosphatidylethanol in cells prelabelled with [3H]myristic acid and stimulated in the presence of 1% (v/v) ethanol; this metabolic pathway, however, proved to be a minor one leading to generation of phosphatidic acid (PtdOH) during cell stimulation, whereas DG production by the sequential action of PtdCho-specific PLD and PtdOH phosphohydrolase was not observed. Studies on cells which were double-labelled with [3H]myristic acid and [14C]arachidonic acid indicated that within 15 s of stimulation DG is uniquely derived from PtdIns(4,5)P2, whereas PtdCho is the major source at later times. Evidence is provided that rapid and selective conversion of phosphoinositide-derived DG into PtdOH may play an important role in determining the temporal accumulation profile of DG from the above-mentioned sources.
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PMID:Muscarinic stimulation of SK-N-BE(2) human neuroblastoma cells elicits phosphoinositide and phosphatidylcholine hydrolysis: relationship to diacylglycerol and phosphatidic acid accumulation. 838 Sep 86

The effects of protein kinase C (PKC) activation on muscarinic receptor-mediated phosphoinositide and Ca2+ signalling were examined in the human neuroblastoma, SH-SY5Y. Carbachol evoked rapid transient elevations of Ins(1,4,5)P3 and intracellular [Ca2+] followed by lower sustained elevations. Phorbol 12,13-dibutyrate (PDBu) preferentially attenuated transient phases. Removal of the transplasmalemmal Ca2+ gradient coupled with depletion of intracellular Ca2+ stores with thapsigargin also reduced carbachol-mediated Ins(1,4,5)P3 accumulation. Under these conditions, PDBu virtually abolished Ins(1,4,5)P3 responses to carbachol thereby implicating both Ca(2+)- and PKC-sensitive components. PDBu also reduced agonist-mediated accumulation of inositol phosphates and depletion of lipids, thereby eliminating an effect of PKC on Ins(1,4,5)P3 metabolism or phosphoinositide synthesis. In electroporated cells, PDBu inhibited Ins(1,4,5)P3 accumulation mediated by carbachol or guanosine 5'-[gamma-thio]-triphosphate, the latter indicating that some PDBu-sensitive elements were downstream of the receptor. The PKC inhibitor, Ro-318220, protected against PDBu but did not enhance responses to maximal concentrations of carbachol, indicating no feedback inhibition by agonist-activated PKC. Muscarinic antagonist activity of Ro-318220 complicated such assessment at low agonist concentrations. Carbachol or PDBu induced cytosol to membrane translocation of PKC alpha. This was faster and possibly greater with PDBu, which may explain the lack of feedback by agonist-activated PKC. These results indicate that, in SH-SY5Y cells, PDBu activation of PKC preferentially inhibits rapid muscarinic receptor-mediated phosphoinositide and Ca2+ responses via suppression of PtdIns(4,5)P2 hydrolysis. This is at least partially through inhibition of Gq-protein/phosphoinositidase C coupling. However, at least at high agonist concentrations, a major agonist-mediated PKC feedback is not present in these cells.
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PMID:Contrasting effects of phorbol ester and agonist-mediated activation of protein kinase C on phosphoinositide and Ca2+ signalling in a human neuroblastoma. 867 Jan 70

In this study we have quantitatively assessed the basal turnover of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and M3-muscarinic receptor-mediated changes in phosphoinositides in the human neuroblastoma cell line, SH-SY5Y. We demonstrate that the polyphosphoinositides represent a minor fraction of the total cellular phosphoinositide pool and that in addition to rapid, sustained increases in [3H]inositol phosphates dependent upon the extent of receptor activation by carbachol, there are equally rapid and sustained reductions in the levels of polyphosphoinositides. Compared with phosphatidylinositol 4-phosphate (PtdIns(4)P), PtdIns(4,5)P2 was reduced with less potency by carbachol and recovered faster following agonist removal suggesting protection of PtdIns(4,5)P2 at the expense of PtdIns(4)P and indicating specific regulatory mechanism(s). This does not involve a pertussis toxin-sensitive G-protein regulation of PtdIns(4)P 5-kinase. Using wortmannin to inhibit PtdIns 4-kinase activity, we demonstrate that the immediate consequence of blocking the supply of PtdIns(4)P (and therefore PtdIns(4,5)P2) is a failure of agonist-mediated phosphoinositide and Ca2+ signaling. The use of wortmannin also indicated that PtdIns is not a substrate for receptor-activated phospholipase C and that 15% of the basal level of PtdIns(4,5)P2 is in an agonist-insensitive pool. We estimate that the agonist-sensitive pool of PtdIns(4,5)P2 turns over every 5 s (0.23 fmol/cell/min) during sustained receptor activation by a maximally effective concentration of carbachol. Immediately following agonist addition, PtdIns(4,5)P2 is consumed >3 times faster (0.76 fmol/cell/min) than during sustained receptor activation which represents, therefore, utilization by a partially desensitized receptor. These data indicate that resynthesis of PtdIns(4,5)P2 is required to allow full early and sustained phases of receptor signaling. Despite the critical dependence of phosphoinositide and Ca2+ signaling on PtdIns(4,5)P2 resynthesis, we find no evidence that this rate resynthesis is limiting for agonist-mediated responses.
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PMID:Differential regulation of muscarinic acetylcholine receptor-sensitive polyphosphoinositide pools and consequences for signaling in human neuroblastoma cells. 947 53

The naturally occurring beta-carbolines exert psychotropic actions in humans and have numerous behavioral effects in animals. The known in vitro activities of these substances do not provide a satisfactory explanation for their in vivo effects. The present study was undertaken to explore the possibility of a specific signal transduction pathway. The human neuroblastoma cell line SH-SY5Y was used as a model system. High-affinity binding sites for [3H]norharman (synonymous: beta-carboline) were detected. Pharmacological characterization revealed displacement of the ligand by beta-carbolines, to a weaker extent by indoleamines, but not by opioids, muscarinic receptor agonists, metabotropic glutamate receptor agonists or several peptide neurotransmitters. Inositol phosphate accumulation was only slightly affected by the beta-carbolines. However, the action of carbachol was clearly facilitated in a dose-dependent and pertussis toxin-insensitive manner. Pretreatment of the cells with Clostridium difficile toxin B blocked the facilitating effect of the beta-carbolines by concentrations which did not affect the action of carbachol alone. This suggests that low molecular weight GTP-binding proteins are involved in the facilitating action of the beta-carbolines. This mechanism was further supported by experiments measuring the concentrations of phosphatidylinositol phosphates after various activating compounds. In conclusion, the facilitating effect of beta-carbolines on inositol phosphate accumulation could play a part in the actions of beta-carbolines and may be produced by stimulating the generation of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), the key component in the activation of phosphoinositide-phospholipase C.
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PMID:The natural beta-carbolines facilitate inositol phosphate accumulation by activating small G-proteins in human neuroblastoma cells (SH-SY5Y). 951 50

The pleckstrin homology domain of phospholipase Cdelta1 (PH(PLCdelta)) binds Ins(1,4,5)P(3) and PtdIns(4,5)P(2) specifically, and can be used to detect changes in Ins(1,4,5)P(3) in single cells. A fusion construct of PH(PLCdelta) and enhanced green fluorescent protein (EGFP-PH(PLCdelta)) associates with the plasma membrane due to its association with PtdIns(4,5)P(2). However, PH(PLCdelta) has greater affinity for Ins(1,4,5)P(3) than PtdIns(4,5)P(2), and translocates to the cytosol as Ins(1,4,5)P(3) levels rise. Prolonged activation of group I metabotropic glutamate receptor 1alpha expressed in Chinese-hamster ovary cells or endogenous M(3) muscarinic receptors in SH-SY5Y neuroblastoma cells gave an initial transient peak in translocation, followed by a sustained plateau phase. This closely followed changes in cell population Ins(1,4,5)P(3) mass, but not PtdIns(4,5)P(2) levels, which decreased monophasically, as determined by radioreceptor assay. Translocation thus provides a real-time method to follow increases in Ins(1,4,5)P(3). Graded changes in Ins(1,4,5)P(3) in Chinese-hamster ovary-lac-mGlu1alpha cells could be detected with increasing glutamate concentrations, and dual loading with fura 2 and EGFP-PH(PLCdelta) showed that changes in intracellular Ca(2+) concentration closely paralleled Ins(1,4,5)P(3) production. Moreover, Ins(1,4,5)P(3) accumulation and intracellular Ca(2+) mobilization within single cells is graded in nature and dependent on both agonist concentration and receptor density.
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PMID:Single-cell imaging of graded Ins(1,4,5)P3 production following G-protein-coupled-receptor activation. 1133 45

ARCN1, KIAA0638, TREH, DDX6, BLR1, BCL9L, UPK2, DLNB13, DLNB14, RPS25, SBDN, G6PT1, HYOU1, VPS11, HMBS, H2AFX, DPAGT1, KIAA0285, MIZF, ABCG4, NOD9, PDZK2, CBL, MCAM, RNF26, C1QTNF5, MFRP, USP2, THY1, and PVRL1 genes are located within the commonly deleted region of neuroblastoma at human chromosome 11q23.3. Here, we characterized the KIAA0638 gene within the 11q23.3 region by using bioinformatics. Because human KIAA0638 gene was homologous to human LL5B gene encoding LL5beta protein, KIAA0638 was designated LL5A gene encoding LL5alpha protein. LL5A isoform 1 (FLJ00141 type) consists of exons 1-12, 14-21 and 23, while LL5A isoform 2 (KIAA0638 type) consists of exon 1-23. LL5A isoform 1 was the major transcript among LL5A isoforms generated due to alternative splicing. Nucleotide sequence of mouse Ll5a cDNA was determined by assembling CB522359 EST and 5'-truncated mKIAA0638 cDNA. Human LL5alpha isoform 2 showed 94.4 and 35.9% total-amino-acid identity with mouse Ll5alpha and human LL5beta, respectively. LL5alpha proteins consist of Forkhead associated (FHA) domain, bipartite nuclear localization signal (NLS), Chromosome segregation ATPases (SMC) domain, and Pleckstrin homology (PH) domain. LL5alpha proteins were homologous to PtdIns(3,4,5)P3 sensor protein LL5beta in the SMC and PH domains, and were also homologous to KIF1A, KIF1B, KIF13A, KIF13B, KIF14, and SNX23 proteins in the FHA domain. LL5alpha protein might be a transducer of PtdIns(3,4,5)P3 levels to the intracellular trafficking system.
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PMID:Identification and characterization of human LL5A gene and mouse Ll5a gene in silico. 1453 93

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