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)

In order to clone the D1 dopamine receptor linked to adenylyl cyclase activation, the polymerase chain reaction was used with highly degenerate primers to selectively amplify a cDNA sequence from NS20Y neuroblastoma cell mRNA. This amplification produced a cDNA fragment exhibiting considerable sequence homology to guanine nucleotide-binding (G)-protein-coupled receptors that have been cloned previously. To characterize this cDNA further, a full-length clone was isolated from a rat striatal library by using the cDNA fragment as a probe. Sequence analysis of this cDNA clone indicated that it is indeed a member of the G-protein-coupled receptor family and exhibits greatest homology with the previously cloned catecholamine receptors. Northern blot analysis of various neural tissues revealed a transcript of approximately 4 kb that was predominantly located in the striatum with lesser amounts in the cortex and retina. In contrast, no mRNA was detected in the cerebellum, hippocampus, olfactory bulb, mesencephalon, or pituitary. In situ hybridization analysis also revealed a high abundance of mRNA in the striatum as well as in the olfactory tubercle. To establish the identity of this cDNA, we performed transient expression experiments in COS-7 cells. [3H]SCH-23390, a D1-selective radioligand, exhibited specific, saturable binding only in cells that were transfected with this cDNA. Competition binding analysis with a variety of dopaminergic ligands demonstrated a D1 dopaminergic pharmacology. In addition, dopamine as well as other D1-selective agonists stimulated cAMP accumulation in transfected COS-7 cells. We conclude that we have cloned a cDNA encoding the D1 dopamine receptor linked to the activation of adenylyl cyclase activity.
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PMID:Molecular cloning and expression of a D1 dopamine receptor linked to adenylyl cyclase activation. 216 56

Extracellular application of lysophosphatidic acid (LPA) elevated intracellular Ca(2+) concentration ([Ca(2+)](i)) in human SH-SY5Y neuroblastoma cells. The maximal response to LPA occurred between 0. 1 and 1 microM, at which point [Ca(2+)](i) was increased by approx. 500 nM. This increase was of similar magnitude to that caused by the muscarinic acetylcholine receptor agonist methacholine (MCh), although the initial rate of release by LPA was slower. Both LPA and MCh released Ca(2+) from intracellular stores, as assessed by inhibition of their effects by thapsigargin, a blocker of endoplasmic reticular Ca(2+) uptake, and by the persistence of their action in nominally Ca(2+)-free extracellular medium. Similarly, both agonists appeared to stimulate store-refilling Ca(2+) entry. MCh produced a marked elevation in cellular Ins(1,4,5)P(3) and stimulated [(3)H]InsP accumulation in the presence of Li(+). In contrast, LPA failed to stimulate detectable phosphoinositide turnover. Chronic down-regulation of Ins(1,4,5)P(3) receptor (InsP(3)R) proteins with MCh did not affect Ca(2+) responses to LPA. In addition, heparin, a competitive antagonist of InsP(3)Rs, blocked Ca(2+)-mobilization in permeabilized SH-SY5Y cells in response to MCh or exogenously added Ins(1,4,5)P(3), but failed to inhibit Ca(2+)-release induced by LPA. Elevation of [Ca(2+)](i) elicited by LPA was blocked by guanosine 5'-[beta-thio]-diphosphate, indicating that this agonist acts via a G-protein-coupled receptor. However, pertussis toxin was without effect on LPA-evoked [Ca(2+)](i) responses, suggesting that G(i/o)-proteins were not involved. In the absence of extracellular Ca(2+), N,N-dimethylsphingosine (DMS, 30 microM), a competitive inhibitor of sphingosine kinase, blocked LPA-induced Ca(2+) responses by almost 90%. In addition, MCh-induced Ca(2+) responses were also diminished by the addition of DMS, although to a lesser extent than with LPA. We conclude that LPA mobilizes intracellular Ca(2+)-stores in SH-SY5Y cells independently of the generation and action of Ins(1,4,5)P(3). Furthermore, the Ca(2+)-response to LPA appears to be dependent on sphingosine kinase activation and the potential generation of the putative second messenger sphingosine 1-phosphate.
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PMID:Lysophosphatidic acid-mediated Ca2+ mobilization in human SH-SY5Y neuroblastoma cells is independent of phosphoinositide signalling, but dependent on sphingosine kinase activation. 1049 10

The Cytosensor microphysiometer device (Molecular Devices, Sunnyvale, CA) is capable of detecting small changes in cellular metabolism in response to specific bioactive ligands by measuring the extracellular acidification rate (ECAR). By measuring the ECAR we were able to detect responses of tissue culture cell lines to a variety of sweet- and bitter-tasting compounds. We examined in detail the responses of the NG108-15 (mouse neuroblastoma x rat glioma hybrid) and SK-N-MC (human neuroepithelioma) cell lines. We determined that NG108-15 cells were consistently very responsive to several potent sweeteners and bitter compounds, such as sodium saccharin, guanidino- sweeteners, denatonium benzoate, quinine, and ranitidine. These compounds could evoke changes in cellular metabolism (measured as ECAR) that were rapid in onset, saturable with respect to ligand concentration, and sensitive to several inhibitors of G-protein-coupled receptor signaling pathways. In sharp contrast, the neuroepithelioma SK-N-MC did not respond to any of the sweet or bitter compounds. Rapid changes in ECAR were easily detectable in both cell lines with the calcium ionophore A23187. Bradykinin elicited changes in the ECAR only in the NG108-15 cell line, which is known to express the B2 receptor. The changes in ECAR of the NG108-15 cell line in response to sweet and bitter taste compounds suggest these cells may expresses a receptor(s) specific for small sapid molecules.
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PMID:Cellular responses of NG108-15 and SK-N-MC lines to sweet and bitter tastants as measured by extracellular acidification rates. 1116 15

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15-deoxy-PGJ(2)), a naturally occurring ligand, activates the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma has been found to induce cell differentiation in such cells as adipose cells and macrophages. Herein, we investigated whether 15-deoxy-PGJ(2) has neuronal cell differentiation and possible underlying molecular mechanisms. Dopaminergic differentiating PC-12 cells treated with 15-deoxy-PGJ(2) (0.2 to 1.6 microM) alone showed measurable neurite extension and expression of neurofilament, a marker of cell differentiation. However, a much greater extent of neurite extension and expression of neurofilament was observed in the presence of NGF (50 ng/ml). In parallel with its increasing effect on the neurite extension and expression of neurofilament, 15-deoxy-PGJ(2) enhanced NGF-induced p38 MAP kinase expression and its phosphorylation in addition to the activation of transcription factor AP-1 in a dose-dependent manner. Moreover, pretreatment of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), a specific inhibitor of p38 MAP kinase, inhibited the promoting effect of 15-deoxy-PGJ(2) (0.8 microM) on NGF-induced neurite extension. This inhibition correlated well with the ability of SB203580 to inhibit the enhancing effect of 15-deoxy-PGJ(2) on the expression of p38 MAP kinase and activation of AP-1. The promoting ability of 15-deoxy-PGJ(2) did not occur through PPAR-gamma because synthetic PPAR-gamma agonist and antagonist did not change the neurite-promoting effect of 15-deoxy-PGJ(2). In addition, contrast to other cells (embryonic midbrain and neuroblastoma SK-N-MC cells), PPAR-gamma was not expressed in PC-12 cells. Other structure-related prostaglandins (PGD(2) and PGE(2)) acting via a cell surface G-protein-coupled receptor (GPCR) did not increase basal or NGF-induced neurite extension. Moreover, GPCR (PGE(2) and PGD(2) receptors) antagonists did not alter the promoting effect of 15-deoxy-PGJ(2) on neurite extension and activation of p38 MAP kinase, suggesting that the promoting effect of 15-deoxy-PGJ(2) may not be mediated by GPCR either. These data demonstrate that activation of p38 MAP kinase in conjunction with AP-1 signal pathway may be important in the promoting activity of 15-deoxy-PGJ(2) on the differentiation of PC-12 cells.
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PMID:Activation of p38 mitogen-activated protein kinase and activator protein-1 during the promotion of neurite extension of PC-12 cells by 15-deoxy-delta12,14-prostaglandin J2. 1260 68

Vasoactive intestinal peptide (VIP) is a neurotransmitter with neurotropic effects. VIP functions through two distinct G-protein-coupled receptor subtypes (VPAC1 and VPAC2). We have demonstrated expression of VPAC1 in pediatric nervous system tumors, including medulloblastoma arising in the cerebellum and neuroblastoma arising in the adrenal medulla. More recently, we have reported the differentiation of neuroblastoma cells by upregulation of VIP type 1 receptor suggesting a role for VPAC1 in neuronal development. To understand the molecular mechanisms regulating VPAC1 expression in both cerebellum and adrenal medulla, we have cloned the human VPAC1 gene and sequenced 2.6-kb of the 5'-flanking sequence. Expression of the luciferase reporter gene under the control of this 2.6-kb human VPAC1 promoter was induced 35-fold in a human medulloblastoma cell line (DAOY) and 36-fold in a human neuroblastoma cell line (SKNSH). Analysis of 5'-unidirectional deletion derivatives of the 2.6-kb fragment demonstrated that a 241-bp sequence immediately upstream of the VPAC1 coding region retains high activity, suggesting that it contains the core promoter region. Quantitative RT-PCR analysis demonstrated that VPAC1 is expressed in mouse cerebellar and adrenal tissues. The VPAC1 promoter also directed expression of a reporter gene in cerebellum and adrenal medulla in transgenic mice. Along with our previous findings, these results suggest that VPAC1 may play a functional role in development of both cerebellum and adrenal medulla.
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PMID:VIP receptor 1 (VPAC1) promoter targets the expression of a reporter gene to cerebellum and adrenal medulla in transgenic mice. 1459 9

CMKLR1 (chemoattractant-like receptor 1) is a G-protein-coupled receptor implicated in cartilage and bone development and is expressed in organs like the parathyroid gland, brain, and lung. The receptor is also expressed in dendritic cells and in macrophages where it acts as a co-receptor for entry of HIV/SIV isolates into human CD4(+) cells. Recently, a protein named "chemerin" (also known as TIG2) was isolated from human inflammatory fluids and hemofiltrate and found to be the endogenous ligand for CMKLR1. We have previously described the genomic organization of the cmklr1 gene and characterized its promoter in mouse neuroblastoma NB4 1A3 cells. In the present study we identify a second transcript, cmklr1b, in mouse microglia BV2 cells. Cmklr1b is transcribed from an alternative promoter with a transcription start site located 6780 bp downstream of the previously identified exon 1 (cmklr1a). The cmklr1b promoter lacks a TATA box but contains two CCAAT boxes in opposite directions. 5' Deletion analysis of the promoter region in BV2 cells using a luciferase reporter gene assay indicates two regions, between 623-755 bp and 56-125 bp upstream of transcription start site, to be important for promoter function. The proximal promoter region includes both CCAAT boxes, and site-directed mutagenesis separately within these elements revealed that only the forward CCAAT element was important for transcription. Although the forward CCAAT element is essential for transcription electrophoretic mobility shift and super-shift assays demonstrated that both CCAAT elements actually bind nuclear proteins from BV2 cells and identified the binding factor as NFY. Real-time reverse transcriptase-PCR experiments of cmklr1b expression in all-trans retinoic acid (ATRA)- stimulated BV2 cells showed strong up-regulation of receptor transcript. Luciferase reporter gene assay of the promoter in ATRA-stimulated BV2 cells confirmed that transcriptional activity of the cmklr1b promoter is increased by ATRA. However, deletion analysis could not identify an ATRA-responsive element within the promoter region suggesting that gene activation is likely to occur through alternative mechanisms. The results emphasise a possible role of cmklr1 in bone modelling.
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PMID:The mouse chemerin receptor gene, mcmklr1, utilizes alternative promoters for transcription and is regulated by all-trans retinoic acid. 1579 32

In this study, we investigate the molecular mechanisms by which acute orphanin FQ/nociceptin (OFQ/N), acting through the nociceptin opioid peptide (NOP) receptor, desensitizes the mu-opioid receptor. We described previously the involvement of protein kinase C and G-protein-coupled receptor kinases (GRK) 2 and 3 in OFQ/N-induced mu receptor desensitization. Because phosphorylation of the mu receptor triggers the successive regulatory mechanisms responsible for desensitization, such as receptor uncoupling, internalization, and down-regulation, we investigated the ability of OFQ/N to modulate [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO)-induced mu receptor phosphorylation in BE(2)-C human neuroblastoma cells transfected with epitope-tagged mu receptors. OFQ/N treatment (100 nM, 60 min) potentiated DAMGO-induced mu receptor phosphorylation; inhibition of GRK2 or protein kinase C concomitant with OFQ/N treatment blocked the OFQ/N-mediated increase in DAMGO-induced phosphorylation. Inclusion of the NOP antagonist peptide III-BTD during OFQ/N pretreatment blocked the potentiation of DAMGO-induced phosphorylation by OFQ/N, which is consistent with the potentiation being mediated via actions of the NOP receptor. In addition, in cells expressing mu receptors in which the GRK-mediated phosphorylation site Ser(375) was mutated to alanine, OFQ/N treatment failed to potentiate DAMGO-induced mu receptor phosphorylation and failed to desensitize the mu receptor. However, DAMGO-induced mu receptor phosphorylation and OFQ/N-induced mu receptor desensitization occurred in cells expressing mu receptors lacking non-GRK phosphorylation sites. These data suggest that OFQ/N binds to NOP receptors and activates protein kinase C, which then increases the ability of GRK2 to phosphorylate the agonist-occupied mu receptor, heterologously regulating homologous mu receptor desensitization.
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PMID:Orphanin FQ/nociceptin potentiates [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin-Induced mu-opioid receptor phosphorylation. 1589 Aug 42

Calcitonin gene-related peptide is a 37 amino acid neuropeptide. Although calcitonin gene-related peptide activates a G-protein-coupled receptor, recent evidence suggests that calcitonin gene-related peptide induces more complex signaling cascades including the activation of MAP kinases [Eur J Pharmacol; 389:125-130 (2000), Neuropeptides; 34:229-233 (2000)]. However, the molecular mechanisms of this activation still remain to be elucidated. For the first time we applied a proteomics approach in order to identify molecular targets of calcitonin gene-related peptide downstream signaling in the neuroblastoma cell line SK-N-MC and identified proteins that changed either their expression, location, or their post-translational modifications in a time-dependent manner after calcitonin gene-related peptide stimulation.
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PMID:Proliferative effect of calcitonin gene-related peptide is induced by at least five proteins as identified by proteome profiling. 1731 53

mu-Opioid receptors (MORs) are G-protein-coupled receptors (GPCRs) that mediate the physiological effects of endogenous opioid neuropeptides and opiate drugs such as morphine. MORs are coexpressed with neurokinin 1 receptors (NK1Rs) in several regions of the CNS that control opioid dependence and reward. NK1R activation affects opioid reward specifically, however, and the cellular basis for this specificity is unknown. We found that ligand-induced activation of NK1Rs produces a cell-autonomous and nonreciprocal inhibition of MOR endocytosis induced by diverse opioids. Studies using epitope-tagged receptors expressed in cultured striatal neurons and a neuroblastoma cell model indicated that this heterologous regulation is mediated by NK1R-dependent sequestration of arrestins on endosome membranes. First, endocytic inhibition mediated by wild-type NK1Rs was overcome in cells overexpressing beta-arrestin2, a major arrestin isoform expressed in striatum. Second, NK1R activation promoted sequestration of beta-arrestin2 on endosomes, whereas MOR activation did not. Third, heterologous inhibition of MOR endocytosis was prevented by mutational disruption of beta-arrestin2 sequestration by NK1Rs. NK1R-mediated regulation of MOR trafficking was associated with reduced opioid-induced desensitization of adenylyl cyclase signaling in striatal neurons. Furthermore, heterologous regulation of MOR trafficking was observed in both amygdala and locus ceruleus neurons that naturally coexpress these receptors. These results identify a cell-autonomous mechanism that may underlie the highly specific effects of NK1R on opioid signaling and suggest, more generally, that receptor-specific trafficking of arrestins may represent a fundamental mechanism for coordinating distinct GPCR-mediated signals at the level of individual CNS neurons.
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PMID:Neurokinin 1 receptors regulate morphine-induced endocytosis and desensitization of mu-opioid receptors in CNS neurons. 1912 99

Invasion of the nervous system and neuronal spread of infection are critical, but poorly understood steps in the pathogenesis of prion diseases. We have thus analyzed the internalization and signal transduction of the neurotoxic fragment of the prion protein PrP(106-126) in the rat neuroblastoma cell line B104 by fluorescence microscopy and quantification by ELISA and in primary neuronal cells from mice. Phospholipase D (PLD) is known to be an enzyme involved in the regulation of secretion, endocytosis and receptor signalling. We determined the PLD activity using a transphosphatidylation assay and could show that PLD is involved in PrP(106-126) internalization. The determination of receptor activity via quantification of ERK1/2 phosphorylation and cAMP level measurement verified the PrP(106-126)-induced signal transduction in B104 cells and primary neuronal cells. PrP(106-126)-induced a decrease in cAMP level in neuronal cells. These studies indicate the involvement of PLD in PrP(106-126)-endocytosis and mediated cellular signalling by an unidentified inhibitory G-protein-coupled receptor and may allow the development of therapeutic agents interfering with prion uptake and/or PLD function using PLD as a possible pharmaceutical target.
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PMID:Internalization and signal transduction of PrP(106-126) in neuronal cells. 1962 74

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