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)

Upon differentiation with retinoic acid of the human neuroblastoma cells SH-SY5Y into mature neurons, opioid drugs become highly effective in suppressing prostaglandin E1 (50% inhibition)- and forskolin (70% inhibition)-stimulated adenylate cyclase activity, which was assessed by measuring cyclic AMP accumulation in intact cells. Whereas the SH-SY5Y cells carry both mu and delta receptors in a ratio of mu/delta approximately equal to 5/1, the response is predominantly mediated by the mu receptor. Morphine acts as a strong agonist with an EC50 of 50 to 100 nM which falls into the therapeutic range expected for narcotic analgesic effects mediated by the mu receptor. Narcotic analgesic drugs with only partial agonism fail to evoke full response, which suggests that this cell model could provide a rapid screening assay for narcotic analgesic efficacy. Continued exposure of the cells to morphine resulted in partial tolerance within 12 hr with a 4-fold shift of morphine's EC50 to higher concentrations, whereas longer morphine exposure did not cause any further shift. Thus, the differentiated SH-SY5Y cells provide a suitable system for studying the molecular mechanisms of the narcotic analgesics.
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PMID:Efficacy and tolerance of narcotic analgesics at the mu opioid receptor in differentiated human neuroblastoma cells. 283 42

Opioid receptor activity in neuroblastoma x glioma NG108-15 hybrid cell membranes was attenuated by acid phosphatase purified by high performance liquid chromatography and devoid of protease activity. Treatment of membranes with this phosphatase decreased opioid inhibition of adenylate cyclase and this effect was potentiated by the presence of the opioid agonist during the phosphatase treatment. Phosphatase treatment did not affect the number of opioid receptors but it did alter the distribution of receptors among affinity states, by increasing the percentage of receptors in the low affinity state. The similarities between these effects and desensitization of the opioid receptor, during chronic opioid treatment, are discussed.
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PMID:Modification of opioid receptor activity by acid phosphatase in neuroblastoma x glioma NG108-15 hybrid cells. 283 85

Primary cultures of pure populations of neuronal or glial cells from the striatum, the cerebral cortex, and the mesencephalon of the mouse embryo were used to look for the presence of opiate receptors coupled to adenylate cyclase. Leu-enkephalin inhibited cAMP production in membranes of embryonic striatal neurons but not in those of other cell types examined. Mu and delta opiate receptors seemed to be coupled negatively to adenylate cyclase in embryonic striatal neurons. It was found that DTLET (a selective delta agonist), as well as DAGO (a selective mu agonist), inhibited cAMP production on these cells. DTLET but not, however, DAGO produced a similar effect on homogenates from the adult rat striatum and on membranes from the neuroblastoma x glioma hybrid cell line NG 108-15, two preparations known to possess only delta receptors negatively coupled to adenylate cyclase. The selective kappa agonist U 50.488 was ineffective on all types of membrane preparations used. The inhibitory effects of both DTLET and DAGO on basal adenylate cyclase activity in striatal neurons were reversed by naloxone with a similar efficacy. Two other selective mu agonists, trimu 5 and morphiceptin, inhibited cAMP production in membranes of striatal neurons as well. The nonadditivity of the inhibitory effects of DTLET and DAGO on basal or forskolin-induced activation of adenylate cyclase suggested that mu and delta receptors were colocalized on a similar subpopulation of striatal cells in primary culture. These cells possess dopaminergic receptors of the D1 subtype as well since the amplitude of the inhibitory effects of DTLET and DAGO on cAMP production was increased in the presence of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mu and delta opiate receptors coupled negatively to adenylate cyclase on embryonic neurons from the mouse striatum in primary cultures. 284 21

The molecular basis of opioid tolerance/dependence has long eluded researchers, but recent advances in receptor regulation have suggested a useful conceptual approach to the problem. In NG108-15 neuroblastoma x glioma hybrid (NG) cells, opioid agonists inhibit adenylate cyclase in a dose-dependent, naloxone-antagonizable fashion. Chronic treatment with opioid agonists results in a series of molecular processes that, in a tolerance-like fashion, counteract this inhibition. These processes include desensitization and down-regulation of receptors and an increase in adenylate cyclase activity. Opioid inhibition of adenylate cyclase and opioid receptor down-regulation also have been observed in the brain. However, most studies have found that the receptors coupled to adenylate cyclase are not of the mu type, which are thought to be the primary mediators of opioid analgesia. Down-regulation has been observed for both mu and delta opioid receptors in the brain. However, in most cases, the time course of down-regulation is not correlated with that for tolerance development, and chronic morphine treatment does not result in down-regulation. Thus, opioid receptors in the brain, like those in NG cells, are subject to dynamic regulation by agonists, which probably has an important role in their function. However, it remains to be established that opioid receptor regulation is the basis of opioid tolerance and dependence.
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PMID:Role of receptor regulation in opioid tolerance mechanisms. 284 42

Incubation of the neuroblastoma x glioma hybrid cell line NG108-15 in tissue culture with dibutyryl cyclic AMP (1 mM) for up to 8 days produced a morphological differentiation of the cells, during which they extended neurite-like processes. Pertussis-toxin-catalysed ADP-ribosylation indicated that amounts of guanine-nucleotide-binding proteins (G-proteins), which are substrates for this toxin, were approximately doubled in membranes from the 'differentiated' cells in comparison with the control cells. Immunoblotting of membranes derived from either untreated or dibutyryl cyclic AMP-treated cells with anti-peptide antisera specific for the alpha subunits of the pertussis-toxin-sensitive G-proteins Gi and Go demonstrated that amounts of these G-proteins were reciprocally modulated during the differentiation process. In comparison with the untreated cells, the amount of Gi in the 'differentiated' cells was decreased, whereas the amount of Go was substantially increased. Stimulation of high-affinity GTPase activity in response to opioid peptides, which in this cell line interact with an opioid receptor of the delta subclass, was much decreased, and inhibition of adenylate cyclase activity was almost entirely attenuated in the 'differentiated'-cell membranes in comparison with membranes of untreated cells. Opioid receptor number was also decreased in membranes of the dibutyryl cyclic AMP-treated cells in comparison with the control cells. These data demonstrate that relatively small changes in the observed pattern of pertussis-toxin-catalysed ADP-ribosylation of membranes can mask more dramatic alterations in amounts of the individual pertussis-toxin-sensitive G-proteins, and further demonstrate the importance of methodologies able to discriminate between the different gene products.
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PMID:Differential regulation of amounts of the guanine-nucleotide-binding proteins Gi and Go in neuroblastoma x glioma hybrid cells in response to dibutyryl cyclic AMP. 285 96

Previous studies in this laboratory have demonstrated that a cloned neuroblastoma cell line (N18TG2) responds to delta 9-tetrahydrocannabinol (THC), the major psychoactive product of marihuana, with an attenuation of cyclic AMP accumulation that results from an inhibition of adenylate cyclase. The requirement for the Gi regulatory protein, stereoselectivity, pharmacologic specificity and cell selectivity of this response suggest that a receptor for cannabimimetic compounds may be associated with adenylate cyclase in the neuroblastoma cell. Presented here is a comprehensive investigation of cellular effects of chronic exposure to cannabimimetic agents. Short-term exposure to either delta 9-THC or the more potent nantradol analog, desacetyllevonantradol (DALN), at doses up to 100 microM did not compromise the plating efficiency of the cells. Cells that were exposed to 1 microM delta 9-THC (maximally effective for inhibiting cyclic AMP production) for 24 hr in a serum-free medium were shown to accumulate the drug but not to metabolize it. Exposure to 10 microM delta 9-THC or DALN for up to 48 hr failed to significantly affect cell growth rate or protein content per cell. The gross morphology of cannabinoid-treated cells was not altered at the light or the electron microscope level. The cellular organelles and membranes appeared intact, with no remarkable differences from control cells. The inhibition of cyclic AMP accumulation in response to cannabimimetic drugs was diminished in cells treated with delta 9-THC or DALN for 24 hr. This desensitization was homologous because both delta 9-THC and DALN responses were attenuated after exposure to either cannabimimetic drug.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of adenylate cyclase by chronic exposure to cannabimimetic drugs. 285 42

Bordetella pertussis, the pathogen responsible for whooping cough, releases a soluble calmodulin-sensitive adenylate cyclase into its culture medium. Recently, Confer and Eaton [Confer, D., & Eaton, J. (1982) Science (Washington, D.C.) 217, 948-950], as well as Hanski and Farfel [Hanski, E., & Farfel, Z. (1985) J. Biol. Chem. 290, 5526-5536], have shown that crude extracts from B. pertussis containing adenylate cyclase activity cause elevations in intracellular cAMP when incubated with human neutrophils or lymphocytes. These investigators proposed that the bacterial enzyme enters animal cells and catalyzes the formation of cAMP from intracellular ATP. In this study, B. pertussis adenylate cyclase was purified to remove contaminating islet activating protein and examined for its effects on intracellular cAMP levels of human erythrocytes and N1E-115 mouse neuroblastoma cells. In both cases, the enzyme catalyzed the formation of intracellular cAMP. Addition of calmodulin to the adenylate cyclase preparations completely inhibited formation of intracellular cAMP catalyzed by the bacterial enzyme, indicating that cAMP was not synthesized extracellularly and then taken up by the cells. These experiments illustrate that the bacterial enzyme does enter animal cells and that the enzyme-calmodulin complex does not.
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PMID:Calmodulin inhibits entry of Bordetella pertussis adenylate cyclase into animal cells. 286 77

The cellular mechanism of action of the cannabimimetic drugs is examined using cultured cells. In membranes from N18TG2 neuroblastoma cells and the neuroblastoma X glioma hybrid cells, NG108-15, the psychoactive cannabinoid drugs and their nantradol analogs could inhibit adenylate cyclase activity. This response was not observed in either the soluble adenylate cyclase from rat sperm or membrane-bound adenylate cyclases from C6 glioma or S49 lymphoma cells. This cellular selectivity provides further evidence for the existence of specific receptors for the cannabimimetic compounds. Receptor-mediated inhibition of adenylate cyclase requires the presence of a guanine nucleotide-binding protein complex, Gi. Gi can be functionally inactivated as a result of an ADP-ribosylation modification catalyzed by pertussis toxin. The present study demonstrates that pertussis toxin treatment of cells abolished the cannabimimetic response in intact cells and in membranes derived therefrom. The action of pertussis toxin required NAD+ as substrate for in vitro modification of neuroblastoma membranes. Furthermore, pertussis toxin was able to catalyze the labeling of a neuroblastoma membrane protein in vitro using [32P] NAD+ under conditions similar to those by which attenuation of the cannabimimetic inhibition of adenylate cyclase could be demonstrated. This evidence demonstrates the requirement for a functional Gi in the action of cannabimimetic drugs.
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PMID:Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. 286 5

Because the antitumor drug caracemide causes neuropsychiatric effects in patients, we investigated its effects on the neurochemistry of cultured neuroblastoma cells (murine clone N1E-115). The drug caused a transient elevation in the level of [3H]cyclic GMP that was not blocked by receptor antagonists or by desensitization of histamine or muscarinic receptors. The EC50 for the response to caracemide was 635 microM. Preincubation of cells with caracemide led to the inhibition of muscarinic receptor-mediated [3H]cyclic GMP formation with an IC50 of 450 microM. Caracemide inhibited basal guanylate cyclase activity in homogenates noncompetitively with a Ki value of 162 microM. The drug also inhibited sodium nitroprusside-stimulated guanylate cyclase in homogenates. Caracemide did not inhibit basal adenylate cyclase activity in either intact cells or homogenates, but inhibited adenylate cyclase activated by prostaglandin E1 (PGE1) or forskolin. The muscarinic receptor-mediated reduction of PGE1-stimulated [3H]cyclic AMP formation was not affected. The Ki for the inhibition of PGE1-activated adenylate cyclase in homogenates was 110 microM. Caracemide was a competitive inhibitor of acetylcholinesterase with a Ki value of 8 microM. The drug did not inhibit, but slightly stimulated, monoamine oxidase activity in N1E-115 cells. The results indicate that caracemide can affect several neurochemical systems in neural cells in culture in a way that correlates with its neuropsychiatric effects. The N1E-115 clone thus appears to be useful for evaluating some of the molecular pharmacological effects of drugs interacting with the nervous system.
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PMID:Effect of the antitumor drug caracemide on the neurochemistry of murine neuroblastoma cells (clone N1E-115). 287 11

With the use of cultured murine neuroblastoma cells (clone N1E-115), the authors studied the effects of chronic ethanol on prostaglandin E, (PGE1)-mediated cyclic AMP formation, adenylate cyclase activity and [3H]PGE1 binding. Whereas acute exposure of these cells to ethanol potentiates the PGE1 response, exposure of cells, for as little as 1 day, to 100 mM ethanol resulted in a diminished responsiveness to PGE1 compared with that in acutely treated cells. This apparent tolerance was well developed by day 4, and, by day 7, treated cells had a diminished response to PGE1 when assayed in the absence of ethanol. To achieve the same level of PGE1-mediated cyclic AMP synthesis as acutely exposed cells, chronically exposed cells required higher concentrations of ethanol. With 7 to 10 days of treatment, there was a modest (10-13%) increase in basal, PGE1- and forskolin-stimulated adenylate cyclase activity in membranous preparations, a 28 to 40% increase in high-affinity [3H]PGE1 binding to membranes with no change in Kd or in the ability of 5'-guanylimidodiphosphate to reduce this binding and a 155% increase in [3H]PGE1 binding to intact cells with no change in Kd. Thus, chronic exposure of N1E-115 cells to ethanol resulted in tolerance to its effects on the PGE1 receptor system, and this tolerance was accompanied by apparently paradoxical changes in PGE1-stimulated cyclic AMP synthesis and [3H]PGE1 binding.
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PMID:Effects of chronic exposure to ethanol on the prostaglandin E1 receptor-mediated response and binding in a murine neuroblastoma clone (N1E-115). 287 32


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