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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of an excitatory amino acid, glutamate, and of ionotropic and metabotropic glutamate receptor agonists on the levels of free intracellular calcium, and their specific receptor binding in human SH-SY5Y neuroblastoma cells were studied. The calcium response was always biphasic, except for AMPA, suggesting both stimulatory and inhibitory effects on free intracellular calcium upon glutamate receptor stimulation, both with ionotropic and metabotropic glutamate receptor agonists. Specific binding of glutamate and other glutamate receptor agonists, together with the biphasic calcium response, suggests that human SH-SY5Y neuroblastoma cells express both ionotropic and metabotropic glutamate receptors. These findings shed new light on the use of human SH-SY5Y neuroblastoma cells as a human neuronal tumor cell model.
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PMID:Excitatory amino acid-induced slow biphasic responses of free intracellular calcium in human neuroblastoma cells. 768 86

Na+-K+-2Cl- cotransporters are important in renal salt reabsorption and in salt secretion by epithelia. They are also essential in maintenance and regulation of ion gradients and cell volume in both epithelial and nonepithelial cells. Expression of Na+-K+-2Cl- cotransporters in brain tissues is high; however, little is known about their function and regulation in neurons. In this study, we examined regulation of the Na+-K+-2Cl- cotransporter by the excitatory neurotransmitter glutamate. The cotransporter activity in human neuroblastoma SH-SY5Y cells was assessed by bumetanide-sensitive K+ influx, and protein expression was evaluated by Western blot analysis. Glutamate was found to induce a dose- and time-dependent stimulation of Na+-K+-2Cl- cotransporter activity in SH-SY5Y cells. Moreover, both the glutamate ionotropic receptor agonist N-methyl-D-aspartic acid (NMDA) and the metabotropic receptor agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) significantly stimulated the cotransport activity in these cells. NMDA-mediated stimulation of the Na+-K+-2Cl- cotransporter was abolished by the selective NMDA-receptor antagonist (+)-MK-801 hydrogen maleate. trans-ACPD-mediated effect on the cotransporter was blocked by the metabotropic receptor antagonist (+)-alpha-methyl-(4-carboxyphenyl)glycine. The results demonstrate that Na+-K+-2Cl- cotransporters in neurons are regulated by activation of both ionotropic and metabotropic glutamate receptors.
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PMID:Stimulation of Na+-K+-2Cl- cotransporter in neuronal cells by excitatory neurotransmitter glutamate. 973 Sep 61

In order to specify the nature of interactions between the analgesic compound nefopam and the glutamatergic system, we examined the effects of nefopam on binding of specific ligands on the three main subtypes ionotropic glutamate receptors: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), or quisqualic acid (QA) and kainic acid (KA) in rat brain membrane preparations. Functionally, we investigated the effects of nefopam against the seizures induced by agonists of these excitatory glutamate receptors in mice. Since the synaptic release of glutamate mainly depends upon the activation of membrane voltage-sensitive sodium channels (VSSCs), the nature of interactions between nefopam and these ionic channels was studied by evaluating the effects of nefopam on binding of 3H-batrachotoxinin, a specific ligand of the VSSCs in rat brain membrane preparations. The functional counterpart of the binding of nefopam on VSSCs was evaluated by its effects on the 22Na uptake-stimulated by veratridine on human neuroblastoma cells and in the maximal electroshock test in mice. Nefopam showed no affinity for the subtypes of ionotropic glutamate receptors up to 100 microM. On the other hand, nefopam was effective against NMDA, QA and KA induced clonic seizures in mice. Nefopam displaced 3H-batrachotoxinin and inhibited the uptake of 22Na in the micromolar range and it protected mice against electroshock induced seizures. Nefopam may block the VSSCs activity: consequently, at the presynaptic level, this effect led to a reduction of glutamate release and at the postsynaptic level, it led to a decrease of the neuronal excitability following activation of the glutamate receptors.
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PMID:Nefopam blocks voltage-sensitive sodium channels and modulates glutamatergic transmission in rodents. 1519 35

Extracellular nucleotides exert a variety of biological actions through different subtypes of P2 receptors. Here we characterized in the human neuroblastoma SH-SY5Y cells the simultaneous presence of various P2 receptors, belonging to the P2X ionotropic and P2Y metabotropic families. Western blot analysis detected the P2X1,2,4,5,6,7 and P2Y1,2,4,6, but not the P2X3 and P2Y12 receptors. We then investigated which biological effects were mediated by the P2Y4 subtype and its physiological pyrimidine agonist UTP. We found that neuronal differentiation of the SH-SY5Y cells with dibutiryl-cAMP increased the expression of the P2Y4 protein and that UTP itself was able to positively interfere with neuritogenesis. Moreover, transient transfection and activation of P2Y4 also facilitated neuritogenesis in SH-SY5Y cells, as detected by morphological phase contrast analysis and confocal examination of neurofilament proteins NFL. This was concurrent with increased transcription of immediate-early genes linked to differentiation such as cdk-5 and NeuroD6, and activity of AP-1 transcription family members such as c-fos, fos-B, and jun-D. Nevertheless, a prolonged activation of the P2Y4 receptor by UTP also induced cell death, both in naive, differentiated, and P2Y4-transfected SH-SY5Y cells, as measured by direct count of intact nuclei and cytofluorimetric analysis of damaged DNA. Taken together, our data indicate that the high expression and activation of the P2Y4 receptor participates in the neuronal differentiation and commitment to death of SH-SY5Y cells.
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PMID:The metabotropic P2Y4 receptor participates in the commitment to differentiation and cell death of human neuroblastoma SH-SY5Y cells. 1564

Agonists of kainate receptors (KARs) cause both the opening of the associated ion channels and the activation of signalling pathways driven by G-proteins and PKC. Here we report the existence of an unknown mechanism of KAR autoregulation, involving the interplay of this two signalling mechanisms. Repetitive activation of native KARs evoked the rundown of the ionotropic responses in a manner that was dependent on the activation of PKC. Experiments on recombinant GluR5 expressed in neuroblastoma cells indicated that KARs trigger the activation of PKC and induce the internalization of membrane receptors. This phenomenon depends on the PKC-mediated phosphorylation of serines 879 and 885 of the GluR5-2b subunits, since mutation of these two residues abolished internalization. These results reveal that the non-canonical signalling of KARs is associated with a sensitive mechanism that detects afferent activity. Such a mechanism represents an active way to limit overactivation of the KAR system, by regulating the number of KARs in the cell membrane.
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PMID:PKC-dependent autoregulation of membrane kainate receptors. 1789 3

Nociceptin (N/OFQ) is involved in neuronal excitability and in certain types of seizures. Kainate-induced seizures are associated with increased N/OFQ release in the rat thalamus and hippocampus, causing down-regulation of the N/OFQ receptor (NOP). In this study, we used the neuroblastoma SH-SY5Y cell line as a model to investigate the effects of kainate on NOP receptor density and gene expression. Exposure to kainate (10-50 microM) for 3 h did not affect NOP receptor density. In contrast, a NOP Bmax down-regulation was detected in cells exposed to 10 microM kainate for both 6 and 24 h. Moreover, our data show that kainate causes a decrease in NOP mRNA levels after 3, 6, and 24 h, an effect blocked by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These findings show that kainate is able to affect the NOP system, both at biosynthesis and receptor density levels in SH-SY5Y cells, and that the kainate ionotropic receptor can contribute to the regulation of the NOP receptor. These data are in agreement with data obtained in vivo and provide new evidence concerning the existence of a cross-talk between NOP and kainate receptors, leading to an interplay between glutamate and N/OFQ circuits.
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PMID:Kainic acid down-regulates NOP receptor density and gene expression in human neuroblastoma SH-SY5Y cells. 1828 84

Nuclear factor-kB (NF-kB) is a family of DNA-binding proteins that are important regulators involved in immune and inflammatory responses, as well as in cell survival and apoptosis. In the nervous system NF-kB is activated under physiological and pathological conditions including learning and memory mechanisms and neurodegenerative diseases. NF-kB is activated in neurons in response to excitotoxic, metabolic and oxidative stress and there is a body of evidence to suggest that glutamate induces NF-kB by the main ionotropic glutamate receptors. In the present study, 3 nitroproprionic acid (3NP), an irreversible inhibitor of succinate dehydrogenase (SD, complex II) has been employed to provide an experimental model of Huntington's disease (HD). Specifically, we described 3NP-induced activation of NF-kB and of iNOS and nNOS genes in striatal treated slices. To aim to better understand the relationship between these identified dysregulated genes and mitochondrial dysfunction, we investigated in SK-N-MC human neuroblastoma cells following 3NP treatment, whether NF-kB nuclear translocation and activation might be involved in the mechanisms by which 3NP leads to transcriptional activation of NOS genes. These results are relevant to more precisely define the role of NF-kB in neuronal cells and better understand its putative involvement in neurodegeneration.
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PMID:NF-kB/NOS cross-talk induced by mitochondrial complex II inhibition: implications for Huntington's disease. 1832 71

Emerging evidence suggests a role for glutamate and its receptors in the biology of cancer. This study was designed to systematically analyze the expression of ionotropic and metabotropic glutamate receptor subunits in various human cancer cell lines, compare expression levels to those in human brain tissue and, using electrophysiological techniques, explore whether cancer cells respond to glutamate receptor agonists and antagonists. Expression analysis of glutamate receptor subunits NR1-NR3B, GluR1-GluR7, KA1, KA2 and mGluR1-mGluR8 was performed by means of RT-PCR in human rhabdomyosarcoma/medulloblastoma (TE671), neuroblastoma (SK-NA-S), thyroid carcinoma (FTC 238), lung carcinoma (SK-LU-1), astrocytoma (MOGGCCM), multiple myeloma (RPMI 8226), glioma (U87-MG and U343), lung carcinoma (A549), colon adenocarcinoma (HT 29), T cell leukemia cells (Jurkat E6.1), breast carcinoma (T47D) and colon adenocarcinoma (LS180). Analysis revealed that all glutamate receptor subunits were differentially expressed in the tumor cell lines. For the majority of tumors, expression levels of NR2B, GluR4, GluR6 and KA2 were lower compared to human brain tissue. Confocal imaging revealed that selected glutamate receptor subunit proteins were expressed in tumor cells. By means of patch-clamp analysis, it was shown that A549 and TE671 cells depolarized in response to application of glutamate agonists and that this effect was reversed by glutamate receptor antagonists. This study reveals that glutamate receptor subunits are differentially expressed in human tumor cell lines at the mRNA and the protein level, and that their expression is associated with the formation of functional channels. The potential role of glutamate receptor antagonists in cancer therapy is a feasible goal to be explored in clinical trials.
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PMID:Expression of glutamate receptor subunits in human cancers. 1952 64

ATP, via purinergic P2X receptors, acts as a neurotransmitter and modulator in both the central and peripheral nervous systems, and is also involved in many biological processes, including cell proliferation, differentiation and apoptosis. Previously, we have reported that P2X7 receptor inhibition promotes axonal growth and branching in cultured hippocampal neurons. In this article, we demonstrate that the P2X7 receptor negatively regulates neurite formation in mouse Neuro-2a neuroblastoma cells through a Ca2+/calmodulin-dependent kinase II-related mechanism. Using both molecular and immunocytochemical techniques, we characterized the presence of endogenous P2X1, P2X3, P2X4 and P2X7 subunits in these cells. Of these, the P2X7 receptor was the only functional receptor, as its activation induced intracellular calcium increments similar to those observed in primary neuronal cultures, exhibiting pharmacological properties characteristic of homomeric P2X7 receptors. Patch-clamp experiments were also conducted to fully demonstrate that ionotropic P2X7 receptors mediate nonselective cation currents in this cell line. Pharmacological inhibition of the P2X7 receptor and its knockdown by small hairpin RNA interference resulted in increased neuritogenesis in cells cultured in low serum-containing medium, whereas P2X7 overexpression significantly reduced the formation of neurites. Interestingly, P2X7 receptor inhibition also modified the phosphorylation state of focal adhesion kinase, Akt and glycogen synthase kinase 3, protein kinases that participate in the Ca2+/calmodulin-dependent kinase II signalling cascade and that have been related to neuronal differentiation and axonal growth. Taken together, our results provide the first mechanistic insight into P2X7 receptor-triggered signalling pathways that regulate neurite formation in neuroblastoma cells.
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PMID:Ca2+/calmodulin-dependent kinase II signalling cascade mediates P2X7 receptor-dependent inhibition of neuritogenesis in neuroblastoma cells. 1968 70

Apoptosis is a major mechanism for cell death in the nervous system during development. P2X(7) nucleotide receptors are ionotropic ATP receptors that mediate cell death under pathological conditions. We developed an in vitro protocol to investigate the expression and functional responses of P2X(7) nucleotide receptors during retinoic acid (RA)-induced neuronal differentiation of human SH-SY5Y neuroblastoma cells. Neuronal differentiation was examined measuring cellular growth arrest and neuritic processes elongation. We found that SH-SY5Y cells treated for 5 days with RA under low serum content exhibited a neuron-like phenotype with neurites extending more than twice the length of the cell body and cell growth arrest. Concurrently, we detected the abolishment of intracellular-free calcium mobilization and the down-regulation of P2X(7) nucleotide receptor protein expression that protected differentiated cells from neuronal cell death and reduced caspase-3 cleavage-induced by P2X(7) nucleotide receptor agonist. The role of P2X(7) nucleotide receptors in neuronal death was established by selectively antagonizing the receptor with KN-62 prior to its activation. We assessed the involvement of protein kinases and found that p38 signaling was activated in undifferentiated after nucleotide stimulation, but abolished by the differentiating RA pretreatment. Importantly, P2X(7) receptor-induced caspase-3 cleavage was blocked by the p38 protein kinase specific inhibitor PD169316. Taken together, our results suggest that RA treatment of human SH-SY5Y cells leads to decreased P2X(7) nucleotide receptor protein expression thus protecting differentiated cells from extracellular nucleotide-induced neuronal death, and p38 signaling pathway is critically involved in this protection of RA-differentiated cells.
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PMID:Inhibition of neuronal cell death after retinoic acid-induced down-regulation of P2X7 nucleotide receptor expression. 1988 9


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