UMLS:C0017638 - FACTA Search

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute ethanol treatment of NG108-15 neuroblastoma x glioma hybrid cells results in inhibition of adenosine uptake with consequent increases in extracellular adenosine and intracellular cAMP concentrations. Chronic exposure to ethanol, however, causes heterologous desensitization of receptors coupled to adenylyl cyclase via stimulatory guanine nucleotide regulatory protein. This heterologous desensitization is correlated with a decrease in the amount of protein and mRNA for the GTP-binding subunit of stimulatory guanine nucleotide regulatory protein. In addition, after chronic exposure to ethanol, the adenosine transporter becomes tolerant to acute ethanol inhibition of adenosine uptake, and there is no longer an increase in extracellular adenosine. We have previously shown that extracellular adenosine is required for the development of ethanol-induced heterologous desensitization. To examine the role of adenosine receptors in mediating these responses to ethanol, we used BW A1434U, an adenosine receptor antagonist that does not inhibit nucleoside transport. BW A1434U caused a concentration-dependent inhibition of (-)-N6-(R-phenyl-isopropyl)-adenosine-stimulated cAMP production in NG108-15 cells. BW A1434U also completely blocked acute ethanol-induced increases in intracellular cAMP levels and prevented the development of ethanol-induced heterologous desensitization and the reduction in the GTP-binding subunit of stimulatory guanine nucleotide regulatory protein. In addition, BW A1434U prevented the development of tolerance to ethanol-induced inhibition of adenosine transport. Our results indicate that in NG108-15 cells, adenosine receptors mediate ethanol-induced changed in cAMP signal transduction and adenosine transport and that an adenosine receptor antagonist can block both these acute and chronic affects of ethanol.
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PMID:Adenosine receptors mediate cellular adaptation to ethanol in NG108-15 cells. 796 54

In our earlier studies we have demonstrated that recombinant human interferon-alpha 2A (rHu-IFN-alpha 2A) inhibits hypothalamo-pituitary-adrenocortical (HPA) secretion following both peripheral and central administration. Furthermore, this effect is antagonized by mu-opioid receptor antagonists, suggesting transduction by this subtype of opioid receptors. In the present studies, we demonstrate that this effect is also observed with the hybrid recombinant preparation, rHu-IFN-alpha A/D, and a leucocyte-derived rat IFN-alpha preparation. The inhibitory effects on HPA activity were observed after intraperitoneal (i.p.) injections of rHu-IFN-alpha 2A (10(3) U), rHu-IFN-alpha A/D (10(4) U), and of Rat-IFN-alpha (1 and 10 U). Similar effects were observed with intracerebroventricular (i.c.v.) administration of all three IFN-alpha preparations. No increases in plasma concentrations of corticosterone were observed with doses of rHu-IFN-alpha A/D up to 10(6) U (i.p.) or 7 x 10(5) U (i.c.v.), but increases were found following i.c.v. administration of high doses of Rat-IFN-alpha (10(3) and 5 x 10(3) U). The inhibitory effects of all of the IFN-alpha preparations tested were antagonized by naloxone, but the stimulatory effects of 5 x 10(3) U Rat-IFN-alpha were not. Injections of rHu-IFN-alpha 2A (10(4) U i.p.) to urethane-anesthetized rats decreased the electrical activity of the majority of hypothalamic paraventricular nucleus neurons tested, including putative corticotropin-releasing factor-secreting neurons antidromically identified as projecting to the median eminence. These electrophysiological data suggest that the decreases in HPA activity evoked by IFN-alpha are mediated by a rapid inhibitory effect at the level of the corticotropin-releasing factor-secreting neurons. The sensitivity of many central nervous system effects of IFN-alpha to mu-receptor antagonists strongly suggests that the cytokine serves as an endogenous opioid agonist arising from the immune system. In support of this hypothesis we have shown that SH-SY5Y human neuroblastoma cells, differentiated with retinoic acid treatment to express predominantly mu-receptors, are sensitive to rHu-IFN-alpha 2A in vitro. This sensitivity took the form of a dose-dependent inhibition of forskolin-stimulated adenylyl cyclase activity. The data yielded an IC50 (95% confidence intervals) value of 7.93 (5.70-11.04) nM for this effect. Neither undifferentiated SH-SY5Y cells nor NG108-15 mouse neuroblastoma x rat glioma hybrid cells (expressing delta-receptors) were affected by rHu-IFN-alpha 2A.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of neural and neuroendocrine activity by alpha-interferon: neuroendocrine, electrophysiological, and biochemical studies in the rat. 800 70

In C6 glioma cells, extracellular ATP and other nucleotide analogs stimulated phosphoinositide (PI) breakdown and inhibited isoproterenol-induced cyclic AMP (cAMP) accumulation. The rank orders of potencies of 15 nucleotide analogs for both responses were clearly different. ATP and adenosine 5'-O-(3-thiotriphosphate) are the most potent agonists for stimulating PI hydrolysis; 2-methylthio-ATP (2-MeSATP) is the most potent agonist for inhibiting cAMP accumulation. P1-mediated responses of PI turnover and cAMP formation are not present in C6 glioma cells. Pertussis toxin (PTX) blocked the nucleotide-induced inhibition of cAMP accumulation but exerted no effect on inositol phosphate formation. Short-term treatment with phorbol 12-myristate 13-acetate inhibited both signal transduction pathways. The effects of three P2 purinergic antagonists, suramin, reactive blue and 4,4'-diisothiocyanatostilbene sulfonic acid (DIDS), on ATP- and 2-MeSATP-induced stimulation of PI turnover and inhibition of cAMP formation, respectively, were compared. For stimulating PI turnover, suramin is a competitive antagonist (pA2, 4.4); reactive blue and DIDS are noncompetitive antagonists at 30 microM and 100 microM, respectively. For the inhibition of cAMP formation, reactive blue and DIDS competitively antagonized the response of 2-MeSATP (pA2 values, 6.3 for reactive blue and 5.7 for DIDS); suramin was only slightly effective at 100 microM. It was concluded that the nucleotide receptor is linked to phospholipase C by a PTX-insensitive Gp protein and the P2Y receptor is linked to adenylyl cyclase by a PTX-sensitive Gi protein. Suramin is a competitive antagonist for the nucleotide receptor; reactive blue and DIDS are more selective antagonists for the P2Y receptor.
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PMID:Different signal transduction pathways are coupled to the nucleotide receptor and the P2Y receptor in C6 glioma cells. 801 79

The molecular interfaces between Gs and the beta-adrenergic receptor were investigated using synthetic peptides corresponding to various regions of its alpha subunit, alpha s. These experiments were carried out on saponin-permeable C6 glioma cells in which the beta-adrenergic receptor appears tightly coupled to Gs. Synthetic site-specific peptides from alpha s (corresponding to amino acids 15-29, 354-372, and 384-394) and alpha i (8-22, 315-324, and 345-455) were tested for their ability to interfere with coupling between the beta-adrenergic receptor and Gs. The two carboxyl-terminal peptides from alpha s blocked beta-adrenergic stimulation of adenylyl cyclase in permeable cells. However, only alpha s-354-372 had this effect in C6 membranes. It is suggested that the partial uncoupling of Gs, which occurs subsequent to cell disruption, may be related to a change in the interaction of the alpha s carboxyl terminus with the beta-adrenoreceptor. Two carboxyl-terminal peptides, 354-372 and 384-394, could also mimic the effect of Gs to increase agonist affinity for the beta-adrenergic receptor. In combination, alpha s-354-372 and alpha s-384-394 increased the ability of isoproterenol to compete with 125I-pindolol binding in a partially additive manner. Synthetic peptides from alpha i and amino-terminal peptides from alpha s had no effect on beta-agonist binding, suggesting a high specificity of peptide effects. Two findings suggest that these peptides bind directly to the beta-adrenergic receptor and stabilize its high agonist affinity conformation. First, GTP and hydrolysis-resistant GTP analogs did not alter the high affinity binding in the presence of high concentrations of the peptides. Second, in S49 lymphoma cyc- cells, which lack Gs, these peptides evoked the high affinity agonist binding state of the beta-receptor. Neither peptide had an effect on antagonist binding affinity, as measured by propranolol displacement of 125I-pindolol. These data suggest that at least two regions on the alpha subunit of Gs participate in high affinity Gs binding to the beta-adrenergic receptor. The fact that these small peptides could mimic the holo-Gs effect on the receptor is rather surprising, and the specificity of the effect suggests that the primary and secondary structure of small regions of alpha s contain much of the information for specific interaction with beta-adrenergic receptors.
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PMID:Synthetic peptides as probes for G protein function. Carboxyl-terminal G alpha s peptides mimic Gs and evoke high affinity agonist binding to beta-adrenergic receptors. 806 88

Increasing evidence indicates that heterotrimeric G proteins, and in particular Go, regulate ionic channel activities. In order to investigate the role of Go proteins in the modulation of the Ca2+ influx, C6 glioma cells were stably transfected with alpha o1 cDNA. Expression of the Go1 alpha protein was checked by Bordetella pertussis toxin-catalyzed ADP-ribosylation and Western blots using one- and two-dimensional gel analyses. Three clones were selected based on their degree of Go1 alpha expression. In alpha o1-transfected cells, cAMP accumulations, in response to isoproterenol or forskolin, were lower than in control cells. This inhibitory effect was a function of the amount of expressed Go1 alpha. In contrast, Go1 alpha expression was not followed by a significant inhibition of isoproterenol- or forskolin-stimulated adenylyl cyclase activities in particulate fractions. In C6 parental cells, 50-60% of the isoproterenol-induced cAMP accumulation was dependent on external Ca2+ concentration. This Ca(2+)-dependent cAMP accumulation was related to an induced transient Ca2+ influx. In transfected cells, expression of Go1 alpha inhibited the Ca2+ influx and the Ca(2+)-dependent component of isoproterenol-induced cAMP accumulation. In conclusion, beta-adrenergic agonists stimulate an entry of Ca2+ which exerts a positive feedback on cAMP production, and Go1 alpha blocks this positive feedback by inhibiting the Ca2+ influx.
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PMID:Transfected Go1 alpha inhibits the calcium dependence of beta-adrenergic stimulated cAMP accumulation in C6 glioma cells. 809 96

The purpose of the present investigation was to determine whether the coupling of delta-opioid receptors to multiple G proteins in NG108-15 neuroblastoma x glioma cells is a characteristic limited to only this cell line (because of the high density of delta-opioid receptors) and to ascertain whether there is any correlation between delta-opioid agonist potency to inhibit adenylyl cyclase and to activate G proteins. Interactions between receptors and G proteins were investigated using agonist-stimulated incorporation of the photoreactive GTP analog azidoanilido[alpha-32P]GTP ([alpha-32P]AA-GTP) into G protein alpha subunits, with subsequent separation by urea/sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In NG108-15, NS20Y, and N1E115 cell membranes, four alpha subunits (Gi2 alpha, one isoform of Gi3 alpha, and both isoforms of Go alpha) in the 39-41-kDa region were labeled with [alpha-32P]AA-GTP. The delta-opioid agonist [D-Ala2,D-Leu5]-enkephalin (DADLE) produced a dose-dependent, naloxone-reversible increase of [alpha-32P]AA-GTP incorporation into all four alpha subunit subtypes, in all cell lines tested. In addition, with the single exception of Gi3 alpha in NG108-15 cells, the maximal increases in incorporation of the photoaffinity label into all G alpha subunits induced by DADLE were similar. The Bmax values determined for delta-opioid receptors in NG108-15, NS20Y, and N1E115 cell membranes were 570, 370, and 120 fmol/mg of protein, respectively. Finally, although the IC50 values to inhibit intracellular cAMP production and affinity for DADLE were similar across the three cell lines, the EC50 values to produce labeling of the G alpha subunits between cell lines differed by > 100-fold. In fact, only in NS20Y cells were the IC50 and ED50 values comparable. Firstly, these results suggest that simultaneous coupling of the delta-opioid receptor to multiple G protein alpha subunits occurs in a variety of cell lines that express a range of receptor densities. Secondly, the magnitudes with which delta-opioid receptors interact with available G alpha subunits in response to agonist are approximately the same. Finally, there appears to be no relationship between the potency of agonists to inhibit adenylyl cyclase and that required for activation of G proteins.
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PMID:Interaction of delta-opioid receptors with multiple G proteins: a non-relationship between agonist potency to inhibit adenylyl cyclase and to activate G proteins. 819 Jan 15

Adenine nucleotides inhibited isoproterenol- and forskolin-stimulated cyclic AMP accumulation in C6-2B rat glioma cells. Inhibition occurred in the presence of a phosphodiesterase inhibitor, and no effect of adenine nucleotides was observed in direct measurements of phosphodiesterase activity in intact cells. Pretreatment of C6-2B glioma cells with pertussis toxin blocked the inhibitory effects of P2Y-purinergic receptor agonists. The pharmacological specificity for a series of ATP and ADP analogs (2-methylthioadenosine 5'-triphosphate > or = 2-methylthioadenosine 5'-diphosphate > adenosine 5'-O-(2-thiodiphosphate) > 2-chloro-adenosine 5'-triphosphate = ADP = adenosine 5'-O-(3-thiotriphosphate) > ATP > UTP) was similar to that expected of a P2Y-purinergic receptor; the P2X-purinergic receptor agonists, alpha,beta-methyleneadenosine 5'-triphosphate and beta,gamma-methylene-adenosine 5'-triphosphate, had no effect. Because activation of phospholipase C occurs in response to P2-purinergic receptor activation in many target tissues, the effects of P2Y-receptor agonists on inositol phosphate accumulation were measured in C6-2B cells. No evidence for P2Y-purinergic receptor-mediated regulation of inositol lipid metabolism was observed under conditions where muscarinic cholinergic receptor activation or AIF4-markedly increased inositol phosphate accumulation. These results suggest that a P2-purinergic receptor subtype with distinct signaling properties exists on C6-2B rat glioma cells. Although this receptor expresses the general pharmacological specificity of a phospholipase C-coupled P2Y-purinergic receptor, it may represent a unique receptor subtype since it inhibits adenylyl cyclase.
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PMID:Identification of a P2Y-purinergic receptor that inhibits adenylyl cyclase. 826 74

The activation of P2-purinergic receptors on C6-2B rat glioma cells caused a transient increase in cytosolic-free Ca2+ concentration ([Ca2+]i) as detected by Fura 2 fluorescence ratio imaging of single cells. These purinergic receptors are of the P2U subtype because UTP and ATP were equipotent and substantially more potent than the P2X- and P2Y-selective agonists alpha,beta-methylene ATP and 2-methylthio ATP, respectively. There was homologous desensitization of the Ca2+ responses between UTP and ATP but no heterologous desensitization between these nucleotides and another Ca(2+)-mobilizing receptor agonist, alpha-thrombin. The UTP-induced peak [Ca2+]i rise was insensitive to chelation of extracellular Ca2+ with EGTA. However, the response was abolished after either depletion of intracellular Ca2+ stores with the microsomal Ca(2+)-ATPase inhibitor thapsigargin or blockade of Ca2+ release from intracellular stores with the muscle relaxant dantrolene. The activation of P2U-purinergic receptors and thrombin receptors increased the formation of total inositol phosphates (IPs) and inhibited cAMP accumulation elicited with either the beta-adrenergic receptor agonist (-)-isoproterenol, or forskolin, a direct activator of adenylyl cyclase. UTP- and alpha-thrombin-induced changes in the levels of IPs, cytosolic Ca2+, and agonist-elicited cAMP accumulation were dramatically inhibited (> 80%) by acute treatment of the cells with the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate but not with the inactive ester 4 alpha-phorbol 12,13-didecanoate. We conclude that in C6-2B cells, the increase in [Ca2+]i after activation of P2U-purinergic receptors is primarily a result of IPs-mediated release of Ca2+ from intracellular stores with secondary influx of Ca2+ by capacitative mechanisms. Also, the inhibition by UTP and alpha-thrombin of agonist-elicited cAMP accumulation is mediated through an increase in [Ca2+]i.
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PMID:P2U-purinergic receptors on C6-2B rat glioma cells: modulation of cytosolic Ca2+ and cAMP levels by protein kinase C. 826 55

Incubation of C6 glioma cells in the presence of aminoglutethimide, an inhibitor of cholesterol metabolism, together with either adenosine 3',5'-cyclic monophosphate (cAMP) analogues or agents that increase cAMP synthesis, such as cholera toxin, forskolin, and isoproterenol, stimulated the rate of pregnenolone formation by their isolated mitochondria. This effect of cAMP was blocked by the antagonist (Rp)-cAMPS. The incorporation rate of mevalonolactone into pregnenolone was also increased by the stimulation of adenylyl cyclase activity in intact C6 cells. It is concluded that cAMP stimulates glial cell steroidogenesis by increasing the movement of the substrate, cholesterol, to the mitochondria, where it will be metabolized to pregnenolone by the side chain cleavage cytochrome P450 enzyme.
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PMID:Regulation of C6 glioma cell steroidogenesis by adenosine 3',5'-cyclic monophosphate. 830 Jan 94

To understand the details of regulation of guanine-nucleotide-binding-protein-linked transmembrane cellular-signalling cascades, it is important to know the absolute levels of each polypeptide component and the stoichiometry of their interactions. Amounts of the IP prostanoid receptor, the stimulatory G protein of the adenylyl cyclase cascade (Gs alpha) and the functional complex of Gs alpha with adenylyl cyclase, which acts as the cyclic AMP generator, were measured in membranes of neuroblastoma x glioma hybrid, NG108-15, cells. As measured by the specific binding of [3H]prostaglandin E1, the IP prostanoid receptor was present in some 100,000 copies/cell. Gs alpha assessed by quantitative immunoblotting with recombinantly expressed protein, was present in considerably higher levels (1,250,000 copies/cell). However, the maximal formation of a complex of Gs alpha and adenylyl cyclase represented only some 17,500 copies/cell. The previously established 8:1 stoichiometry of concurrent downregulation of Gs alpha and the IP prostanoid receptor in these cells [Adie, E. J., Mullaney, I., McKenzie, F. R. & Milligan, G. (1992) Biochem. J. 285, 529-536] indicates that full-agonist occupation of the receptor should be able to activate some 65% of the expressed Gs. Despite the potential 70-fold excess of Gs alpha over the Gs alpha/adenylyl cyclase complex, IP prostanoid-receptor-agonist-mediated reduction of Gs alpha levels by some 35% resulted in a 25% reduction in the maximal formation of the Gs alpha/adenylyl cyclase complex. Such results demonstrate that adenylyl cyclase is quantitatively the least highly expressed component of this signalling cascade and suggests that much of the cellular Gs alpha may not have access to adenylyl cyclase.
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PMID:Quantitative stoichiometry of the proteins of the stimulatory arm of the adenylyl cyclase cascade in neuroblastoma x glioma hybrid, NG108-15 cells. 830 80

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