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)

Evidence suggests that nitric oxide (NO) may mediate, at least in part, excitotoxic effects of excessive N-methyl-D-aspartate (NMDA) receptor activation both in vivo and in vitro. In the present experiments, NMDA-induced excitotoxicity has been studied in CHP100 neuroblastoma cell cultures. Application of NMDA (0.25-1.5 mM) produced concentration-dependent cell death. These effects were antagonized by co-application of dizocilpine (MK801), a selective and non-competitive NMDA receptor complex antagonist. Protection from NMDA-induced lethal effects was also afforded by N omega-nitro-L-arginine methyl ester, a potent NO-synthase inhibitor, and by hemoglobin, a NO-trapping agent. In addition, substitution of L-arginine, normally present in the exposure solution with its D-isomer, abolished the cell death induced by the excitotoxin. In conclusion, the present experiments support the suggestion that excitotoxic effects induced by NMDA receptor stimulation involve L-arginine-NO pathway activation.
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PMID:Evidence that CHP100 neuroblastoma cell death induced by N-methyl-D-aspartate involves L-arginine-nitric oxide pathway activation. 128 60

The anti-hypertensive drug ifenprodil is known to interact potently with the alpha 1-adrenergic receptor as well as a number of other second messenger-linked receptors. In addition to these properties, ifenprodil has been shown to prevent glutamate-mediated excitotoxicity via non-competitive antagonism of NMDA receptors [Legendre and Westbrook (1991) Molec. Pharmac. 40: 289-298; Shalaby et al. (1992) J. Pharmac. Exp. Ther. 260: 925-932]. With these things in mind, we have begun to examine the specificity of ifenprodil for various ligand-gated ion channels using electrophysiological methods. While ifenprodil effectively inhibits NMDA-mediated currents in cortical neurons in culture, it does not interact with either kainate or GABA receptors. Surprisingly, ifenprodil also acts as a relatively potent antagonist of the 5-hydroxytryptamine3 (5-HT3) receptor in the NG108-15 neuroblastoma x glioma cell line. Furthermore, several aspects of ifenprodil action on the 5-HT3 receptor resemble its interaction with the NMDA receptor. Namely, inhibition of 5-HT3-mediated cation currents is readily reversible, has relatively slow onset, is non-competitive, and is not voltage dependent. Since most of the known 5-HT3 antagonists are competitive, it is possible that ifenprodil may define a unique modulatory site(s) on this neurotransmitter receptor.
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PMID:Ifenprodil inhibition of the 5-hydroxytryptamine3 receptor. 756 98

In the present study, we have attempted to clarify whether neuroblastoma glioma hybrid NG 108-15 cells (NG cells) possess the NMDA receptor complex using [45Ca2+]influx and [3H]MK-801 binding as functional measures. Glutamate and NMDA dose-dependently increased [45Ca2+]influx and these increases were further enhanced by glycine. Scatchard analysis revealed the presence of a high-affinity binding site for [3H]MK-801 with a KD of 18.8 nM and a Bmax of 0.328 pmol/mg protein. This [3H]MK-801 binding was also increased by NMDA in a dose-dependent manner and this increase was further enhanced by glycine. Both ketamine and MK-801 inhibited glutamate- and NMDA-induced [45Ca2+]influx as well as the increase of [3H]MK-801 binding in a dose-dependent manner. Similarly, Mg2+ and Zn2+ dose-dependently reduced both glutamate-induced [45Ca2+]influx and [3H]MK-801 binding. Spermine, one of the polyamines, showed a biphasic stimulatory effects on glutamate-induced [45Ca2+]influx and [3H]MK-801 binding. These results indicate that NG cells possess a pharmacologically distinct NMDA receptor complex and suggest that these cells may be useful for the analyses on pharmacological and biochemical characteristics of the NMDA receptor complex.
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PMID:Presence of N-methyl-D-aspartate (NMDA) receptors in neuroblastoma x glioma hybrid NG108-15 cells-analysis using [45Ca2+]influx and [3H]MK-801 binding as functional measures. 791

The cytotoxic effects of the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 were studied in human CHP100 neuroblastoma cell cultures. Incubation of neuroblastoma cultures with gp120 (1 pM-10 nM) induces cell death which is not concentration-related. The significant cell death evoked by 10 pM gp120 was prevented by neutralization of the viral protein with a monoclonal anti-gp120 (IgG) antibody. In addition, gp120-induced cytotoxicity was inhibited by [DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] (CGP37849; 100 microM), [(+/-)-3R*, 4as*, 6R*, 8aR*-6-(phosphonomethyl) decahydro-isoquinoline-3-carboxylic acid] (LY274614; 100 microM), MK801 (dizocilpine; 200 nM) and 7-chloro kynurenic acid (100 microM), selective antagonists of the NMDA receptor complex; by contrast, (6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 100 microM), a non-NMDA antagonist, was ineffective. Prevention of the lethality elicited by the HIV-1 coat protein was also obtained by incubating neuroblastoma cells with gp120 in Ca(2+)-free medium. The lethal effects induced by gp120 involve activation of L-arginine-nitric oxide (NO) pathway since these were prevented by haemoglobin (10 microM), a NO-trapping agent, and by D-arginine (1 mM), the less active enantiomer of the endogenous precursor of NO synthesis. Cytoprotection was also afforded by N omega-nitro-L-arginine methyl ester (L-NAME; 200 microM), an inhibitor of NO synthase, and this was reversed by L-arginine (1 mM). Interestingly, indomethacin and flufenamic acid (10 microM), two inhibitors of cyclooxygenase, protected neuroblastoma cells from death induced by gp120. Furthermore, indomethacin prevented the neuroblastoma cell death evoked by exposure of cultures to sodium nitroprusside (SNP; 0.2-1.6 mM), a NO donor. Finally significant cytotoxic effects were observed after incubation of neuroblastoma cells with prostaglandin E2 (0.1-10 microM). In conclusion, the present data suggest that death of human CHP100 neuroblastoma cells in culture produced by gp120 involves NO and PGE2 production.
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PMID:Death of cultured human neuroblastoma cells induced by HIV-1 gp120 is prevented by NMDA receptor antagonists and inhibitors of nitric oxide and cyclooxygenase. 858 64

In order to clarify the role of cytosolic Ca2+ buffering, a property that in living cells is sustained primarily by high affinity binding proteins, in NMDA receptor-sustained neuron excitotoxicity, cultures of the neuroblastoma line CHP 100 (which is known to express the receptor) were loaded with the chelator BAPTA by incubation with various concentrations (0.03-1 microM) of its acetoxymethylester derivative. The effectiveness of the loading in terms of cytosolic buffering was confirmed by fura-2 measurement experiments in which the [Ca2+]i transients induced by cell exposure to ATP were blunted in the initial peak (up to -75%) and also in the following plateau. When the BAPTA-loaded neuroblastoma cells were exposed to NMDA (1 mM), excitotoxicity was reduced dose-dependently up to almost 70%, while the generation of cGMP was inhibited up to completion. The latter result suggested the possible involvement of nitric oxide in the NMDA-induced excitoxicity, a mechanism confirmed by the dose-dependent inhibitory effect induced by the nitric oxide synthase blocker, L-N-(1-iminoethyl)-ornithine, which protected the cells completely when administered at 300 microM. Flow cytometry analysis of DNA revealed that the mechanism of excitotoxicity in CHP100 cells does not involve apoptosis. We conclude that cytosolic Ca2+ buffering, a property known to vary considerably among neuronal cells and to change in some neurons also during ageing, has a general protective effect. Such a protection appears to take place via the blunting of the glutamate-induced [Ca2+]i responses mediated by the NMDA receptor, with prevention of the ensuing overactivation of nitric oxide synthase and of the irreversible derangement of the ionic homeostasis of the cell.
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PMID:Cytosolic Ca2+ buffering, a cell property that in some neurons markedly decreases during aging, has a protective effect against NMDA/nitric oxide-induced excitotoxicity. 876 26

NG108-15 neuroblastoma cells differentiated with 0.1 M of all-trans retinoic acid (RA) were processed for immunohistochemical analysis using polyclonal antisera against the delta opioid receptor (DOR) and the N-Methyl-D-Aspartate receptor (NMDAR1) to determine the cellular sites for possible functional associations between DOR and NMDAR1 receptors. In this study, 6 days of RA treatment resulted in prominent morphological differentiation characterized by the appearance of numerous axon- and dendrite-like processes and formation of networks between the cell clusters. An immunocytochemical approach allowed the demonstration of antibody concentration-dependent differences, not evident in ligand binding studies, in the distribution of DOR and NMDA receptor protein between cell soma and processes. RA-differentiated cultures showed positive DOR-like immunostaining (DOR-LI) throughout the cell bodies as well as on the newly acquired processes. In contrast, NMDAR1-like immunoreactivity (NMDAR1-LI) in the RA-treated cells was detected in the cell soma and processes only with the higher concentration of the antiserum. With the lower concentration of the antibody the NMDAR1-LI was not detected in the processes and was limited to a punctuate subcellular distribution in the soma. The DOR-LI pattern of distribution in NG108-15 cells differentiated with RA appeared to be consistent with the DOR-LI detected in the CNS. The NMDAR1-LI distribution in these cells is similar to brain tissue with respect to its presence on the newly acquired processes. However, it differed from brain in that a much higher abundance of NMDAR1 receptors was observed in the cell soma. This differential distribution of DOR and NMDAR1 receptors in the RA-treated NG108-15 cells could provide a basis for future studies of drug-induced changes in these two receptors.
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PMID:Detection of delta opioid receptor and N-methyl-D-aspartate receptor-like immunoreactivity in retinoic acid-differentiated neuroblastoma x glioma (NG108-15) cells. 898 Dec 41

Coadministration of antagonists of N-methyl-D-aspartate (NMDA) receptor and opioids has been shown to prevent development of opiate tolerance in animal and clinical studies, but its cellular and molecular mechanisms are not understood. In this study, the effect of NMDA on delta-opioid receptor (DOR)-mediated signal transduction was investigated in neuroblastoma x glioma NG108-15 cells that functionally express both DOR and NMDA receptors. Acute incubation of NG108-15 cells with NMDA, a specific agonist of NMDA receptor, significantly attenuated the ability of DOR agonist [D-Pen2, D-Pen5]-enkephalin (DPDPE) to inhibit forskolin-stimulated cAMP production. The attenuation caused by NMDA was dose-dependent, and the EC50 of DPDPE increased 100-fold (from 4.6 nM to 500 nM) after NMDA treatment. The NMDA effect on responsiveness of delta-opioid receptors to DPDPE could be blocked by ketamine, a NMDA receptor-specific antagonist. This NMDA attenuation effect on DOR activity was also observed in neuronal primary cell cultures from fetal mouse brain but not in the Chinese hamster ovary cell line stably transfected with DOR alone. Interestingly, NMDA pretreatment reduced the cellular response to epinephrine but not to that of prostaglandin E1 in NG108-15 cells, which suggests differential modulation of NMDA on different G protein-coupled receptors. Pretreatment of NG108-15 cells with ketamine along with DPDPE greatly attenuated DPDPE-induced acute desensitization of DOR. Furthermore, the specific inhibitors of protein kinase C, either chelerythrine chloride or Go 6979, effectively blocked the NMDA effect, which indicates the involvement of protein kinase C in the process. In conclusion, the activation of NMDA receptors can attenuate acute responsiveness of DOR in neuronal cells, whereas its blockage leads to reduction of DOR desensitization. These results have thus provided an insight into cross-talk between NMDA and opioid signal transduction.
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PMID:Activation of N-methyl-D-aspartate receptor attenuates acute responsiveness of delta-opioid receptors. 910 22

Blockade of N-methyl-D-aspartate (NMDA) receptors by the specific antagonists dizocilpine and (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid on human neuroblastoma SH-SY5Y cells expressing human D21 receptors resulted in a significant increase in the density of D2L receptors. In order to understand the mechanism of dopamine D2L receptor induction following NMDA receptor blockade we used specific protein tyrosine kinase and phosphatase inhibitors to demonstrate their involvement in this interaction. The induction of dopamine D2L receptor was measured by radioreceptor binding assay. The density of the dopamine D2L receptor was increased to 109% by the inhibition of protein tyrosine kinase and prevented by the inhibition of phosphatase 1 or 2A. Inactivation of NMDA receptors might effect the phosphorylation-dephosphorylation states of the regulatory proteins and lead to the induction of the D2L receptor gene.
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PMID:NMDA and dopamine D2L receptor interaction in human neuroblastoma SH-SY5Y cells involves tyrosine kinase and phosphatase. 911 14

The effects of N-methyl-D-aspartate (NMDA) on opioid receptor-mediated G protein activation were explored in neuroblastoma X glioma hybrid (NG108-15) cells. Treatment of the cells with NMDA resulted in a remarkable attenuation of [35S]guanosine-5'-O-(3-thio)triphosphate binding stimulated by [D-Pen2,D-Pen5]-enkephalin (DPDPE), a delta-opioid receptor agonist. The effects of NMDA were dose and time dependent with an IC50 value of 5 nM and could be blocked by NMDA receptor antagonists. After NMDA treatment, the DPDPE dose-response curve shifted to the right (EC50 value increased approximately 7-fold, from 6 to 40 nM), and the maximal response induced by DPDPE was reduced by approximately 60%. The effects of NMDA were reversible, and the DPDPE response could recover within 60 min. The functional responses of delta-, mu-, and kappa-opioid receptors in primarily cultured neurons also were attenuated significantly by NMDA treatment. The inhibitory effects of NMDA on opioid receptor-mediated G protein activation could be blocked by coadministration of the protein kinase C (PKC) inhibitors or by elimination of the extracellular Ca2+. Correspondingly, NMDA treatment of NG108 cells significantly elevated cellular PKC activity and stimulated Gialpha2 phosphorylation. Transient transfection into NG108-15 cells of the wild-type Gialpha2 and a mutated Gialpha2 (Ser144Ala) resulted in a 2-fold increase in DPDPE-stimulated G protein activation. The DPDPE responses were greatly inhibited by NMDA treatment in the wild-type Gialpha2-transfected cells but much less affected in the mutant Gialpha2-transfected cells. In summary, NMDA attenuates opioid receptor/G protein coupling, and this process requires activation of PKC.
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PMID:N-Methyl-D-aspartate attenuates opioid receptor-mediated G protein activation and this process involves protein kinase C. 954 59

Acute incubation of NMDA with neuroblastoma x glioma hybrid (NG108-15) cells or neuroblastoma SK-N-SH cells produced significant attenuation of nociceptin/orphanin FQ (N/OFQ)-induced activation of G protein and inhibition of adenylyl cyclase. The attenuation of N/OFQ signaling by NMDA was dose-dependent, blockable by NMDA antagonists, and not observed in cells lacking NMDA receptors, indicating that the effect of NMDA is mediated by the NMDA receptor. Furthermore, NMDA antagonist pretreatment greatly attenuated N/OFQ-induced acute homologous desensitization of ORL1. Interestingly, the signaling induced by etorphine, an opioid agonist of wide spectrum, was sensitive to NMDA treatment in NG108-15 but insensitive in SK-N-SH cells, suggesting differential modulation of opioid signaling by NMDA. The attenuation effects of NMDA on mu opioid receptor-mediated signaling were also observed.
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PMID:Attenuation of nociceptin/orphanin FQ-induced signaling by N-methyl-D-aspartate in neuronal cells. 955 29


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