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)

Human beta-endorphin 1-31 (beta-END) stimulated low-Km GTPase activity in a concentration-dependent and saturable manner in membranes prepared from the delta opioid receptor-containing hybrid cell line NG108-15 and from the mu opioid receptor-enriched human neuroblastoma cell line SK-N-SH. Naloxone and the delta-selective antagonist, ICI 174,864, blocked the stimulation of the GTPase activity produced by beta-END in NG108-15 cell membranes, whereas only naloxone inhibited the beta-END-induced stimulation in SK-N-SH cell membranes, suggesting that beta-END was acting through both mu and delta opioid receptors. Treatment of the cells with Bordetella pertussis toxin before the preparation of membranes blocked the stimulation of low-Km GTPase by beta-END in both cell lines. Activation of NG108-15 and SK-N-SH low-Km GTPase by beta-END was sodium-dependent, and lithium and potassium were poor promoters of this activation. These results demonstrate that beta-END stimulates the interaction of both mu and delta opioid receptors with B. pertussis toxin-sensitive G-proteins in SK-N-SH and NG108-15 cell membranes, respectively.
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PMID:Effects of beta-endorphin on mu and delta opioid receptor-coupled G-protein activity: low-Km GTPase studies. 132 14

We have measured mu and delta opioid receptor sites on intact SK-N-SH and NG108-15 neuroblastoma cells, respectively, in culture. Use of 125I-beta-endorphin (beta E) as a tracer, together with beta E(6-31) to block high-affinity non-opioid binding in both cell lines, permitted the measurement of cell surface mu and delta opioid receptor sites. Labeling was at delta sites in NG108-15 cells and predominantly at mu sites in SK-N-SH cells. Pretreatment with the mu and delta agonist, DADLE, caused a rapid loss of cell surface delta receptor sites in NG108-15 cells, but failed to reduce significantly mu receptor density in SK-N-SH cells.
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PMID:Rapid agonist-induced loss of 125I-beta-endorphin opioid receptor sites in NG108-15, but not SK-N-SH neuroblastoma cells. 165 8

Cholera toxin treatment (up to 1 microgram/ml, 16 h) of neuroblastoma x glioma hybrid NG108-15 cells produced a decrease of some 35% in both delta opioid receptor-mediated stimulation of high-affinity GTPase activity and inhibition of forskolin-amplified adenylate cyclase. Coincident with these decreases was a down-regulation of some 35% in the delta opioid receptor population. A similar pattern of a decrease in signalling capacity was noted for the alpha 2B-adrenergic receptor in these cells after cholera toxin treatment. Half-maximal effects of cholera toxin on all of the parameters assayed were noted at concentrations between 2 and 5 ng/ml. Neither levels of Gi2, as assessed by immunoblotting with specific antisera, nor the intrinsic activity of the alpha subunit of the guanine-nucleotide-binding protein which acts as the inhibitory G-protein of the adenylate cyclase in these cells, as assessed by guanosine 5'-[beta gamma-imido]triphosphate (Gpp[NH]p)-mediated inhibition of adenylate cyclase, was lowered by cholera toxin treatment. Furthermore, levels of another pertussis toxin-sensitive G-protein (Go) expressed by these cells was also not lowered by cholera toxin treatment. However, as previously noted in other cells [Milligan, Unson & Wakelam (1989) Biochem. J. 262, 643-649], marked down-regulation of the alpha subunit of the stimulatory G-protein (Gs) of the adenylate cyclase cascade was observed in response to cholera toxin treatment. Previous studies [Klee, Milligan, Simonds & Tocque (1985) Mol. Aspects Cell Regul. 4, 117-129] have shown that cholera toxin treatment can result in a decrease in the maximal effectiveness of agonists which function to inhibit adenylate cyclase. These data have been used as evidence to suggest a functional interaction between Gs and 'Gi'. The results provided herein demonstrate that such effects of the toxin can be explained adequately by a decrease in the number of receptors that function to produce inhibition of adenylate cyclase.
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PMID:Cholera toxin impairment of opioid-mediated inhibition of adenylate cyclase in neuroblastoma x glioma hybrid cells is due to a toxin-induced decrease in opioid receptor levels. 167 34

Chronic treatment of neuroblastoma x glioma NG108-15 hybrid cells with the opioid agonist D-Ala,2 D-Leu5-enkephalin (DADLE) induces a homologous desensitization of the delta opioid receptors present in these cells. Since the Kd value of the delta opioid receptor's high-affinity state reflects the potency of the agonist, we examined the effect of receptor desensitization in NG108-15 cells on the percentage of receptor in the high-affinity state. When NG108-15 hybrid cells were treated with 10 or 100 nM DADLE for 4 hr at 24 degrees C, loss of DADLE's ability to inhibit adenylate cyclase was observed. However, when competition binding experiments were carried out with P2P3 membranes isolated from the delta opioid-desensitized hybrid cells, it was determined that 41.7 +/- 3.4% of the total binding sites remained in the high-affinity state, with no apparent alteration in the Kd value of either high- or low-affinity states. Similarly, when NG108-15 cells were treated with 100 ng/ml of pertussis toxin for 3 hr at 37 degrees C, 39.9 +/- 3.6% of the binding sites remained in the high-affinity state. This reduction in the percentage of receptor in high-affinity state was agonist specific, for chronic treatment of hybrid cells with levorphanol, a partial agonist, or the antagonist naloxone did not alter the percentage of opioid receptors in the high-affinity state. Furthermore, the delta opioid receptors remaining in the high-affinity state after chronic DADLE treatment were still sensitive to both Na+ and guanyldylimidodiphosphate, indicating that opioid ligand binding remained coupled to the G-proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of chronic D-Ala,2 D-Leu5-enkephalin or pertussis toxin treatment on the high-affinity state of delta opioid receptor in neuroblastoma x glioma NG108-15 hybrid cells. 184 9

Nine distinct alpha subunits of guanine nucleotide binding proteins (G-proteins) have now been identified by cDNA cloning. Each of these functions to allow transduction of information between hormone-activated receptors in the plasma membrane and effector systems which are either ion channels or enzymes which regulate the intracellular concentration of second messengers. As the individual G-proteins are highly similar in primary sequence, it is pertinent to ask what degree of specificity of interaction each of these display with the various receptors and effector systems. Specificity of tissue location defines that the rod and cone transducins (TD1 and TD2, respectively) act as the coupling proteins between rhodopsin and cone opsins and their cyclic nucleotide phosphodiesterase effectors and that G(olf) is the G-protein which tranduces signals from odorant receptors to adenylate cyclase in olfactory sensory neurones. However, many of the other identified G-proteins are co-expressed in a single tissue or cell. Whilst sensitivity to ADP-ribosylation catalysed by bacterial toxins from Bordetella pertussis and Vibrio cholerae has allowed a further subdivision of the G-protein family, this approach is limited as these toxins have multiple G-protein substrates. As the extreme C-terminus of the alpha subunit of each G-protein appears to be a key domain for the interactions of receptors and G-proteins we have generated a series of G-protein-selective antipeptide antisera against this region and then have used these antisera to attempt to interfere with receptor-G-protein coupling. With this approach we have been able to demonstrate that a delta opioid receptor-mediated inhibition of adenylate cyclase in neuroblastoma x glioma, NG108-15, cell membranes is transduced specifically by Gi2 and in the same cell that alpha 2 adrenergic inhibition of Ca2+ currents is transduced by Go. Similar strategies are likely to be of universal significance, for example in the identification of the G-protein (Gp) which regulates the receptor-mediated activation of phosphoinositidase C. Methods to allow pharmacological manipulation of the levels of expression of various G-proteins in the membranes of cells are also discussed. Such approaches are also likely to assist in the identification of G-proteins of defined functions.
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PMID:The role and specificity of guanine nucleotide binding proteins in receptor-effector coupling. 196 33

Though opioid receptors are more difficult to purify and characterize than other cell surface receptors, significant progress has been made in the past several years. At least a dozen groups have now reported purification of opioid-binding proteins, either in a form that retains ligand-binding properties, or in a covalently bound form. Although there are some discrepancies in the molecular weights of these proteins, it is significant that many investigators have reported a molecular weight of about 60 kd for the receptor, regardless of whether it is of the mu, delta, or kappa type. This finding, together with immunological evidence, suggests that different opioid receptor types may be highly similar, and could conceivably even share a common ligand-binding subunit. Several groups have prepared monoclonal or polyclonal antibodies to purified opioid-binding proteins, which should be useful in mapping the brain regional distribution of the opioid receptors, determining the regions in the peptide involved in ligand binding and association with second messengers, and in determining the relationships among different opioid receptor types. One group has in fact already established an antigenic similarity between a mu-selective opioid-binding protein in mammalian brain, and the delta opioid receptor in NG108-15 neuroblastoma-glioma hybrid cells. One group has reported cloning of the cDNA for a purified opioid-binding protein. Somewhat surprisingly, its predicted amino acid sequence places it in the immunoglobulin superfamily, with strongest homologies to cell-adhesion molecules such as N-CAM. MAG, amalgam and fasciclin II, as well as receptors for peptides such as PDGF and interleukin-6. However, this is consistent with evidence that opioids can modulate cell-cell interactions of monocytes, and provides further support for links between opioids and the immune system. The second messengers mediating opioid actions are still unknown. Opioid agonists affect the activity of adenylate cyclase and ion channels in some tissues, but neither has been shown to mediate opioid analgesia. The sequence homologies of the purified opioid-binding protein OBCAM with tyrosine kinase growth factor receptors suggest additional possibilities for second messengers.
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PMID:Molecular characterization of opioid receptors. 216 Jul 90

Recently we reported the synthesis of the first enantiomeric pair of irreversible opioid ligands [(3S,4R)-(-)- and (3R,4S)-(+)-cis-4, SUPERFIT] and specific interaction of the latter with the delta receptor. Here we report another enantiomeric pair of irreversible opioid ligands, (+)-trans- and (-)-trans-3-methylfentanyl isothiocyanates [(3S,4S)-(+)-trans- and (3R,4R)-(-)-trans-4]. A single-crystal X-ray analysis of the 2,4,6-trinitrobenzenesulfonic acid salt of (+)-trans-3-methyl-N-phenyl-4-piperidinamine [(+)-trans-8] revealed it (and, therefore, 4) to have the trans configuration and the absolute configuration of (+)-trans-8 to be 3S,4S. The (+)-trans enantiomer of 4 was shown to be highly potent and about 10-fold more selective as an acylating agent than (-)-trans-4 for the higher affinity [3H]DADL (delta) binding site in rat brain membranes. In that assay, (+)-trans-4 and (+)-cis-4 were essentially equipotent as affinity ligands, and the levo enantiomers were considerably less potent. (+)-trans-4 was, thus, a potent, subtype-selective acylating agent for the delta opioid receptor in vitro. With membranes from NG108-15 neuroblastoma x glioma hybrid cells, containing only delta receptors, (+)-cis-4 was found to be a little more potent than (+)-trans-4. Similarly, (+)-cis-4 is the most effective inhibitor of adenylate cyclase in these membranes, (+)-trans-4 has weak activity, and the levo enantiomers are inactive. Only (+)-cis-4 was found to have antinociceptive activity in vivo.
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PMID:Probes for narcotic receptor mediated phenomena. 15. (3S,4S)-(+)-trans-3-methylfentanyl isothiocyanate, a potent site-directed acylating agent for the delta opioid receptors in vitro. 254 60

Specific binding properties of the tritium-labeled delta opiate receptor agonist [3H][2-D-penicillamine, 5-D-penicillamine]enkephalin [( 3H][D-Pen2, D-Pen5]enkephalin) were characterized in the rat brain and in a mouse neuroblastoma-rat glioma hybrid cell line (NG 108-15). Saturation isotherms of [3H][D-Pen2, D-Pen5]enkephalin binding to rat brain and NG 108-15 membranes gave apparent Kd values of 1-6 nM. These values are in good agreement with the Kd value obtained from the kinetic studies. The Bmax value in NG 108-15 membranes was 235.3 fmol/mg of protein. An apparent regional distribution of [3H][D-Pen2, D-Pen5]enkephalin binding was observed in the rat brain. A number of enkephalin analogues inhibited [3H][D-Pen2, D-Pen5]enkephalin binding with high affinity (IC50 values of 0.5-5.0 nM) in both NG 108-15 and rat brain membranes. However, putative mu receptor-selective ligands such as morphine, [D-Ala2, MePhe4, Gly5-ol]enkephalin, [MePhe3, D-Pro4]morphiceptin, and naloxone were less effective inhibitors of [3H][D-Pen2, D-Pen5]enkephalin binding in both systems tested. These data suggest that [3H][D-Pen2, D-Pen5]enkephalin is a potent and selective ligand for the delta opioid receptor.
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PMID:Characterization of [3H][2-D-penicillamine, 5-D-penicillamine]-enkephalin binding to delta opiate receptors in the rat brain and neuroblastoma--glioma hybrid cell line (NG 108-15). 298 20

The characteristics of mu and delta opioid receptor sites present in human neuroblastoma SH-SY5Y cells were investigated using [D-Ala2-N-methyl-Phe4-Gly-(01)5]enkephalin (DAGO) and [2-D-penicillamine, 5-D-penicillamine]enkephalin (DPDPE), which are the most selective radioligands available for mu and delta sites, respectively. Scatchard analysis of the saturation isotherms revealed high affinity binding to a single class of sites for both [3H]DAGO (mu) and [3H]DPDPE (delta). [3H]DAGO labeled twice the number of sites compared to the binding capacity of [3H]DPDPE, yielding a mu/delta ratio of 2:1. Selective suppression of [3H]diprenorphine binding by specific opioid "blocking" ligands also showed a predominance of mu receptors, representing 65-70% of the total opioid sites. Competition binding studies carried out with a series of opiates and opioid peptides displayed higher potencies of mu- and delta-selective ligands in displacing the specific binding of [3H]DAGO and [3H]DPDPE, respectively. The [3H]diprenorphine/agonist competition curves were biphasic, indicating the high and low affinity states of mu and delta receptor sites in SH-SY5Y cells. Guanine nucleotide and sodium had differential effects on the agonist affinity and the proportion of high affinity states of mu and delta receptors. The mu and delta receptor sites were shown to be functionally coupled to adenylate cyclase. All of these data support the independent existence of mu and delta receptor types in human neuroblastoma cells. SH-SY5Y cells, therefore, represent a suitable model for investigating opioid-mediated responses in nerve cell populations.
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PMID:Comparative pharmacological properties and functional coupling of mu and delta opioid receptor sites in human neuroblastoma SH-SY5Y cells. 303 97

Phenotypic variability of the human neuroblastoma cell line SK-N-SH was studied with the use of three subclones that interconvert at a slower rate than the parent cell line, i.e., a neuroblast-type subclone (SH-SY5Y), a nonneuronal, strongly substrate adherent subclone (SH-EP), and an intermediate type subclone (SH-IN). Rhodamine-phalloidin staining of actin fibers revealed differences in the cytoskeleton morphology of the three subclones, while the clathrin subunit proteins (heavy and light chains), components of coated vesicles, were invariant. Dramatic differences were observed for the expression of neurotransmitter systems, i.e., the mu and delta opioid receptor, the muscarinic cholinergic receptor and its effect on phosphatidylinositol turnover, and the uptake1 transporter for catecholamines. While these systems were strongly expressed in the parent line and the neuroblast-like clones SH-SY5Y and SH-IN, they were absent or barely detectable in the nonneuronal EP clone. Furthermore, the protooncogenes N- and c-myc were only expressed in the neuroblast containing lines, consistent with their growth characteristics of fully transformed cells. The strong c-myc expression in the absence of c- or N-myc amplification in SK-N-SH, adds a new form of high protooncogene activity in neuroblastoma cell lines. The remarkable differences of neurotransmitter systems and myc expression among the various phenotypes of human neuroblastoma cells should be considered in the therapy of neuroblastoma.
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PMID:Expression of neurotransmitter receptors and myc protooncogenes in subclones of a human neuroblastoma cell line. 304 Feb 40


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