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

The subtype of muscarinic receptor which mediates cAMP attenuation is not established. Therefore, several selective muscarinic antagonists were used to characterize the subtype of muscarinic receptor coupled to the inhibition of hormone-stimulated cAMP accumulation using NG108-15 neuroblastoma x glioma hybrid cells. These cells were prelabeled with [2-3H]-adenine, washed, and resuspended in a culture medium containing the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.5 mM). The labeled cells were preincubated with the different antagonists 12-15 min. before they were challenged with agonists. The formation of [3H]-cAMP was activated by PGE1 (1 microM) or forskolin (1 microM). In all cases, [3H]-cAMP formed was separated and measured. Carbachol (100 microM) and McN-A343 (10 mM) were used as standard muscarinic agonists. These studies gave the following results: a) McN-A343 (10 mM), an M1 receptor agonist, was only a partial agonist causing 40% inhibition of cAMP accumulation indicating that this effect was not mediated by an M1 receptor; b) The M1-selective antagonist, pirenzepine, exhibited low affinity (pA2 6.2) further suggesting that an M1 receptor was not coupled to the attenuation of cAMP accumulation; c) Two selective M2 antagonists (AF-DX 116 and methoctramine) and M3 antagonist (HHSiD) were used to further characterize these muscarinic receptors. The order of all antagonists based on their affinities (pA2 values) could be arranged in the following order: atropine (9.0) > methoctramine (7.6) > HHSiD (6.9) > AF-DX 116 (6.6) > pirenzepine (6.2). HHSiD exhibits the same degree of affinity to M2 receptors of other tissues as it does to those of NG cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Subtype of muscarinic receptor coupled to the attenuation of hormone-stimulated cAMP accumulation in NG108-15 neuroblastoma x glioma hybrid cells. 128 46

We have carried out an extensive pharmacological characterization of muscarinic binding sites in rabbit lung and chicken heart in parallel with M1, M2, and M3 sites, [3H]Pirenzepine, a selective antagonist at M1 receptors, bound saturably and reversibly to membranes from chicken heart and rabbit lung. These binding sites were not M1 receptors, however, because the cardioselective antagonist himbacine had 10-fold higher affinity at these sites than at [3H]pirenzepine sites in rat and rabbit cortex (true M1 sites). We measured the inhibitory potency of 28 antagonists at [3H]N-methylscopolamine-labeled sites in chicken heart, rabbit lung, rat heart (M2 sites), and rat submandibular gland (M3 sites) and at M1 sites in rat cortex. The sites in rabbit lung were different from M1, M2, and M3 sites, because they had moderate to high affinity for M1-selective compounds (pirenzepine and telenzepine), M2-selective compounds (himbacine and methoctramine), and M3-selective compounds (hexahydrosiladifenidol and 4-diphenylacetoxy-N-methylpiperidine methiodide). The sites in chicken heart resembled most those in rabbit lung, with similar high affinity for secoverine, but they were not the same because tropicamide, diphenylacetoxybutynyl dimethylamine, and [3H]-N-methylscopolamine were more potent in rabbit lung. In a further series of experiments, we compared the affinity of six of the most discriminating antagonists in membranes from rabbit lung and NG108-15 cells, a neuroblastoma-glioma cell line reported to express the muscarinic m4 receptor gene. The antagonists had very similar affinities in the two tissues, the largest discrepancy being that pirenzepine was twice as potent in rabbit lung as in NG108-15 cells. Northern blots using probes designed to discriminate between five species of muscarinic receptor RNA detected only m4 mRNA in rabbit lung. We conclude that rabbit lung contains a muscarinic M4 binding site with a quite distinctive pharmacology and that chicken heart contains a receptor with similarities to the M4 sites. This is the first report to characterize native M4 binding sites in a nonneuronal mammalian tissue.
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PMID:Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells. 225 Jun 62

To compare the proportions of four muscarinic receptors in different rat brain regions, we used competition curves with four selective antagonists, at 1-[N-methyl-3H]scopolamine methyl chloride [( 3H]NMS) binding equilibrium and after allowing [3H]NMS dissociation for 35 min. Himbacine and methoctramine were shown to discriminate two muscarinic receptor subtypes having a high affinity for 4-diphenylacetoxy-N-methylpiperidine methiodide and hexahydrosiladifenidol, intermediate affinity for pirenzepine, and low affinity for AF-DX 116. One M4 subtype had a high affinity for himbacine and methoctramine; it was found predominantly in homogenates from rat striatum (46% of total [3H]NMS receptors) and in lower proportion in cortex (33% of [3H]NMS receptors) and hippocampus (16% of [3H]NMS receptors). Its binding properties were identical to those of muscarinic receptors in the neuroblastoma x glioma NG 108-15 hybrid, suggesting that it was encoded by m4 mRNA. The M3 subtype (typically found in rat pancreas, a tissue expressing the m3 mRNA) had a low affinity for himbacine and methoctramine and represented about 10% of all [3H]NMS receptors in rat brain cortex, hippocampus, striatum, and cerebellum. M1 and M2 receptors were identified in rat brain by their high affinity for pirenzepine and AF-DX 116, respectively.
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PMID:Binding of selective antagonists to four muscarinic receptors (M1 to M4) in rat forebrain. 238 34

Activation of muscarinic cholinergic receptors on 1321N1 human astrocytoma cells leads to Ca2+ mobilization as measured by quin 2 fluorescence. Acetylcholine and methacholine were full and potent agonists, while carbachol and muscarine, were fully efficacious but 6- and 10-fold less potent than acetylcholine. The carbachol-induced Ca2+ response was also observed in absence of extracellular Ca2+ and was blocked by muscarinic receptor antagonists but not by organic Ca2+ channel blockers, tetrodotoxin (TTX), tetraethylammonium (TEA) or metal cations, suggesting that Ca2+ is mobilized from intracellular storage sites rather than through plasma membrane ion channels. Muscarinic receptor-mediated Ca2+ release was also detected in kidney epithelial cells but not in rat fibroblasts, glial cells or differentiated neuroblastoma x glioma hybrid cells.
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PMID:Calcium mobilization by muscarinic receptors in human astrocytoma cells: measurements with quin 2. 244 30

Hormonal regulation of Mg2+ influx was examined in the neuroblastoma X glioma hybrid cell line NG108-15 and the skeletal muscle cell line G8 using 28Mg2+. Both cell lines express multiple classes of hormone receptors; in addition, G8 cells can be induced to differentiate from a single myoblast-like cell into fused myotube-like cells. In NG108-15 cells, 2-Cl-adenosine, an adenosine receptor agonist, stimulated Mg2+ influx by about 60%. This effect was not mimicked by norepinephrine or PGE1, agonists at alpha 2-adrenergic and prostaglandin receptors which NG108-15 cells also express. Carbachol, acting through a muscarinic receptor, gave minimal and variable stimulation of Mg2+ influx. The effect of 2-Cl-adenosine was not blocked by theophylline, an adenosine receptor antagonist, and was not mimicked by adenosine analogs selective for either A1 or A2 adenosine receptors, suggesting that a nonclassical adenosine receptor mediates the effect on Mg2+ influx. Theophylline slightly stimulated Mg2+ influx as did the permeable cyclic AMP analog, 8-Br-cyclic AMP. These results indicate that cyclic AMP may influence Mg2+ influx in NG108-15 cells unlike previous results in murine S49 lymphoma cells [Maguire and Erdos, J. biol. Chem. 255: 1030-1035, 1980] where receptor modulation of Mg2+ influx was independent of cyclic AMP. In G8 cells, the nicotinic cholinergic receptor agonist carbachol stimulated Mg2+ influx at the myoblast cell stage but had no effect on Mg2+ influx after cells had formed myotubes. The beta-adrenergic agonist isoproterenol had the opposite effect, stimulating Mg2+ influx in the myotube stage but not in the myoblast stage. Taken together, these results demonstrate that only a subset of receptors expressed by a cell may be coupled to Mg2+ influx, that the regulation of Mg2+ influx differs from cell type to cell type, and finally, that modulation of Mg2+ influx by hormone receptors may change with differentiation.
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PMID:Hormonal regulation of magnesium uptake: differential coupling of membrane receptors to magnesium uptake. 282 11

The recovery of rat muscarinic receptor number from the effects of a specific alkylating ligand, N-[4-(2-chloroethylmethylamino)-2-butynyl]-2-pyrrolidone (BM 123), in three tissues is presented as an exponential function of time. No significant difference was found in the recovery rate constants derived from analysis of recovery time courses in corpus striatum, cerebral cortex and ileal longitudinal muscle. The single rate constant (0.021/hr) was also independent of amount and duration of BM 123 dose. Additional analysis of agonist-defined high and low affinity subsites in cortex revealed that recovery of these populations also followed similar time courses although the alkylation proceeds more slowly for the high affinity sites. The rate constant for recovery of both subsites was 0.029/hr. Recovery from BM 123 alkylation occurred in NG108-15 neuroblastoma X glioma cells. The presence of cycloheximide in the recovery medium did not significantly inhibit this recovery process in the clonal cell line, suggesting that de novo receptor synthesis is unnecessary for regeneration of unalkylated receptors.
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PMID:Spontaneous regeneration of free muscarinic receptor after alkylation by BM 123. I. Recovery in vivo and in cell culture. 291 65

Glioma C62B cells were incubated for 18 h with [1-14C]arachidonic acid. Most (80%) of the added [1-14C] arachidonic acid was taken into the intracellular pool; less than 1% of the intracellular [1-14C]arachidonic acid remained unesterified; the rest was present in glycerophospholipids. Acetylcholine stimulation of the prelabeled cells resulted in the rapid accumulation of free [1-14C]arachidonic acid, presumably liberated by hydrolysis from phospholipids. Labeled unesterified [1-14C]arachidonic acid peaked by 90 s and returned to basal levels by 5 min. Paralleling the transient increase of unesterified [1-14C]arachidonic acid were increases in level of radioactivity in an unidentified lipoxygenase metabolite of arachidonic acid and of radioactive phosphatidic acid. The release of arachidonic acid induced by acetylcholine or carbachol was blocked by muscarinic but not nicotinic receptor antagonists; adrenergic or histaminergic receptor agonists were ineffective at stimulating arachidonic acid liberation. In contrast to the transient effects of stimulation with cholinergic agonists, stimulation with the divalent cation ionophore A23187 resulted in a linear increase in the accumulation of liberated arachidonic acid for at least 1 h. Furthermore, the pattern of metabolites synthesized from arachidonic acid in response to ionophore stimulation was more complex than that observed following cholinergic stimulation and included also several metabolites derived from cyclooxygenase activity. We conclude that muscarinic receptor agonists rapidly induce specific changes in arachidonic acid and phosphatidic acid metabolism in a glioma cell line and suggest that similar responses may occur in glial cells and play a physiologically significant role in neural metabolism.
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PMID:Cholinergic stimulation of arachidonic acid and phosphatidic acid metabolism in C62B glioma cells. 308 4

Although both second messenger response systems are fully functional in both cell lines, activation of muscarinic cholinergic receptors only results in inhibition of adenylate cyclase in NG108-15 neuroblastoma X glioma cells and stimulation of phosphoinositide hydrolysis in 1321N1 human astrocytoma cells. Muscarinic receptors on both cell types were covalently labeled with [3H]propylbenzilylcholine mustard ([3H]PBCM), and the mobilities of the [3H]PBCM-labeled species of both cells were compared by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. 1321N1 and NG108-15 cells each primarily expressed a single [3H]PBCM-labeled species with an apparent size of approximately 92,000 and 66,000 Da, respectively. [3H]PBCM labeling was completely inhibited by 1 microM atropine or by down-regulation of muscarinic receptors by an overnight incubation with carbachol. The apparent size of the [3H]PBCM-labeled species of both cell lines was not altered by treatment with a series of protease inhibitors or by treatment with dithiothreitol and iodoacetamide. Since muscarinic receptors are glycoproteins, the contribution of carbohydrate groups to the difference in apparent size of the [3H]PBCM-labeled proteins was determined by treatment of [3H]PBCM-labeled membranes with endoglycosidase F, an enzyme that removes both complex and high mannose type N-linked carbohydrate chains. Endoglycosidase F treatment reduced the apparent size of the [3H]PBCM-labeled species in 1321N1 cells from 92,000 to approximately 77,000 Da and in NG108-15 cells from 66,000 to 45,000 Da. Neuraminidase produced no further reduction of the apparent size of the [3H]PBCM-labeled species from either cell after endoglycosidase F treatment, suggesting the absence of sialic acid containing O-linked carbohydrate chains on the muscarinic receptors of the two cell lines. The results suggest that different muscarinic receptor proteins may be responsible for the two different biochemical responses to muscarinic receptor activation.
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PMID:[3H]propylbenzilylcholine mustard-labeling of muscarinic cholinergic receptors that selectively couple to phospholipase C or adenylate cyclase in two cultured cell lines. 311 80

(Isobutylthio)adenosine (SIBA, 1) and its derivatives have been shown to produce a variety of biological effects on the basis of the hypothesis that such agents act directly as inhibitors of transmethylation reactions, as inhibitors of S-adenosylhomocysteine hydrolase, or as inhibitors of polyamine biosynthesis. We report here the ability of selected analogues of SIBA to inhibit the binding of the muscarinic antagonist quinuclidinyl benzilate (QNB) to cultured N4TG1 neuroblastoma cells and to antagonize the acetylcholine-induced contraction of guinea pig ileum. The most potent inhibitors were 5'-deoxy-5'-(isobutylthio)-1-deazaadenosine (1-deaza-SIBA, 5) and 5'-deoxy-5'-(isobutylthio)-3-deazaadenosine (3-deaza SIBA, 3), while the parent nucleoside SIBA and the carbocyclic derivative 5'-(isobutylthio)-3-deazaaristeromycin were less active. The same agents had no effect on the nicotinic receptors of NG108-15 neuroblastoma X glioma hybrid cells. The acyclic derivative 9-[[2-(isobutylthio)ethoxy]methyl]adenine, 3-deazaadenosine, 5'-(isobutylthio)tubercidin, and 5'-(isobutylamino)adenosine were inactive at the 1-mM level. These results suggest that SIBA and 3-deaza-SIBA may have profound effect on membrane-mediated phenomenon, including inhibition of muscarinic receptor binding.
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PMID:Inhibition of muscarinic receptor binding and acetylcholine-induced contraction of guinea pig ileum by analogues of 5'-(isobutylthio)adenosine. 387 62

Inhibitory coupling of receptors to adenylate cyclase previously has been shown to be relatively sensitive to inactivation by alkylation with N-ethylmaleimide (NEM). Modification of the inhibitory guanine nucleotide regulatory protein, Ni, has been proposed to be responsible for this effect. The effects of NEM on GTP-sensitive binding of carbachol to muscarinic cholinergic receptors has been compared in a cell line (1321N1 human astrocytoma cells) in which these receptors stimulate phosphoinositide breakdown and in a cell line (NG108-15 neuroblastoma X glioma cells) in which activation of these receptors results in inhibition of adenylate cyclase. Pretreatment of membrane preparations from 1321N1 cells with NEM resulted in a concentration-dependent decrease in the extent of pertussis toxin-catalysed [32P]ADP-ribosylation of a 41 000 Da protein previously proposed to be the alpha subunit of Ni. Under conditions where 32P-labelling of Ni in 1321N1 membranes was reduced by NEM by 90%, no effect was observed on the extent of guanine nucleotide-sensitive high-affinity binding of carbachol to muscarinic cholinergic receptors. In contrast, treatment of NG108-15 membranes with NEM under the same conditions resulted in complete loss of high-affinity guanine nucleotide sensitive binding of carbachol. These results illustrate another difference between the muscarinic receptor population of these two cell lines, and support the previous proposal that muscarinic receptors of 1321N1 cells couple to a guanine nucleotide regulatory protein that is not Ni.
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PMID:Further evidence that muscarinic cholinergic receptors of 1321N1 astrocytoma cells couple to a guanine nucleotide regulatory protein that is not Ni. 392 72


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