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)

Two novel beta-adrenergic myocardial stimulants of general structure: Formula: (see text), where R is a phenyl or benzyl group were investigated for their ability to stimulate and desensitize the cyclic AMP response of C6 glioma cells. Compound ICI 89, 963 (R:phenyl) which elicited less than 1% of the maximum increase in cAMP produced by isoproterenol, was strikingly effective as a desensitizer of the isoproterenol response. This desensitization was markedly reduced by propranolol. Compound ICI 119,033 (R: benzyl) which was a more effective stimulant of cAMP synthesis than ICI 89,963, was also a more effective desensitizer of the isoproterenol response of C6 cells. The kinetics of the desensitization by ICI 89,963 were comparable with those for isoproterenol reaching a maximum in 2 to 3 hours. The data indicate that beta-adrenergic agonists are more potent as desensitizers of the cyclic AMP response than as stimulants of that response.
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PMID:Desensitization of beta receptor mediated cyclic AMP response of cultured fibroblasts by partial agonists. 3 55

C6 glioma cells possess both beta 1- and beta 2-adrenergic receptors. In response to exposure to isoproterenol, these cells down-regulated the mRNA for both beta 1- and beta 2-adrenergic receptors in a manner that indicates an independent regulatory mechanism for each subtype. In particular, the mRNA species for the beta 1-adrenergic receptor initially increased two-fold during the first hour of exposure before decreasing to 40% of initial levels at 4 hours after exposure. In contrast, the beta 2 mRNA species decreased rapidly and monotonically to 20% of initial levels by 2 hours. The unique response to isoproterenol of each subtype was blocked by the appropriate subtype-specific antagonists, betaxolol and ICI 118,551. In addition, beta-adrenergic receptor mRNA down-regulation was observed in association with contact inhibition, suggesting that events other than receptor occupancy can regulate beta-adrenergic receptor mRNA levels.
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PMID:Differential down-regulation of beta 1- and beta 2-adrenergic receptor mRNA in C6 glioma cells. 197 13

We used radioligand binding methods to characterize beta-adrenergic receptors on endothelial cells cultured from adult human iliac vein (HIVE) and bovine fetal aorta (BFAE). For comparison, we also studied the well-characterized C6 glioma cell line (C6). Both human and bovine endothelial cells showed specific saturable binding of [125I]iodopindolol. There was no difference in the binding affinity (KD) of iodopindolol to membranes from the three cell types. However, the beta-receptor density (Bmax) was greater on HIVE cells and BFAE cells than on C6 cells. Displacement of ligand from HIVE and BFAE cells by zinterol or from BFAE cells by ICI 89,406 was consistent with binding to the beta 2-subtype. In contrast, displacement of ligand from C6 cells by zinterol or ICI 89,406 was consistent with binding to both beta 1- and beta 2-subtypes. Exposing BFAE cells in culture to 10 microM isoproterenol for 6 h resulted in a 55% decrease in Bmax without a change in KD. We conclude that 1) human and bovine endothelial cells in culture contain a substantial population of beta-adrenergic receptors, which are predominantly of the beta 2-subtype, and 2) endothelial beta-receptors exhibit downregulation by beta-agonists in culture.
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PMID:Characterization of beta-adrenergic receptors in cultured human and bovine endothelial cells. 284 93

The interactions of the atypical agonists pindolol and celiprolol with beta adrenergic receptors were compared with those of the full agonist, isoproterenol. Studies were carried out using intact cells as well as membranes prepared from C6 glioma cells. Computer-assisted analysis of dose-response curves resulting from the inhibition of the binding of [125I]iodopindolol by the beta-1 and beta-2 selective compounds ICI 89,406 and ICI 118,551 revealed that approximately one-third of the beta adrenergic receptors on these cells were beta-1 receptors. Addition of GTP to the binding assay simplified the dose-response curve for inhibition of the binding of [125I]iodopindolol by isoproterenol and diminished the potency of the agonist. GTP had no effect on the binding of pindolol or celiprolol, suggesting that these drugs do not induce the formation of a ternary complex with the receptor and the guanine nucleotide-binding protein for stimulation of adenylate cyclase activity. When added to the growth medium of intact C6 cells, isoproterenol induced a 40-fold increase in cyclic AMP accumulation. Pindolol and celiprolol, however, caused no elevation of enzyme activity. Addition of isoproterenol to the growth medium of intact cells resulted in an 80% decrease in the density of both beta-1 and beta-2 adrenergic receptors within 8 hr. Growing cells in the presence of pindolol or celiprolol induced a 50% decrease in the density of beta-2 receptors, which was inhibited by beta adrenergic antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective regulation of beta-1 and beta-2 adrenergic receptors by atypical agonists. 286 5

Subclasses of receptors exist for most neurotransmitters. Frequently, two subtypes of receptors coexist in the same tissue and, in some cases, they mediate the same physiological response. In tissues with two classes of binding sites for a given hormone, an estimate of the proportion of each class of binding sites is obtained by inhibiting the binding of a single concentration of a radioligand with a selective unlabeled ligand. Accurate estimates of the density of each class of receptors will only be obtained, however, if the radioligand is entirely nonselective. Selectivity of just 2- to 3-fold can markedly influence the results of subtype analysis. The conclusion that a radioligand is nonselective is usually based on the results of a saturation binding curve. If Scatchard analysis of such data results in a linear plot, then it is concluded that the radioligand is nonselective. However, Scatchard analysis cannot distinguish between a radioligand that is nonselective and one that is slightly selective. The use of a slightly selective radioligand can lead to errors of 50% or more, depending on the concentration of the radioligand relative to the Kd values of the two classes of sites. A new analytical method has been developed that can be used to quantitate 2- to 3-fold differences in the affinity of two distinct classes of binding sites for a radioligand. This new approach requires that a series of inhibition experiments with a selective unlabeled ligand be performed in the presence of increasing concentrations of the radioligand. Analysis of the resulting inhibition curves, utilizing the mathematical modeling program MLAB on the PROPHET system, yields accurate estimates of the density of each class of receptor as well as the affinity of each receptor for the labeled and unlabeled ligands. This approach was used to determine whether 125I-iodopindolol shows selectivity for beta 1- or beta 2-adrenergic receptors. A series of inhibition curves was generated with the unlabeled ligands ICI 89,406 (beta 1-selective) and ICI 118,551 (beta 2-selective), using membranes prepared from C6 glioma cells. These cells contain both beta 1- and beta 2-adrenergic receptors. 125I-Iodopindolol was determined to be 3-fold selective for beta 2-adrenergic receptors. Since the sensitivity of this approach is superior to that of Scatchard analysis, it is likely that other radioligands, previously thought to be nonselective, will be shown to be selective when analyzed by this method.
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PMID:A quantitative method of analyzing the interaction of slightly selective radioligands with multiple receptor subtypes. 287 74

In tissues with two classes of binding sites for a drug, it is common to estimate the proportion of each class of binding site by inhibiting the binding of a radioligand with a selective unlabeled ligand. Accurate estimates of the density of each class of binding site, however, will be obtained only if the radioligand is nonselective or used at a concentration that saturates both classes of binding sites. A method of simultaneous regression analysis of multiple inhibition curves, using the program MLAB on the PROPHET system, was used to quantify the selectivity of radioligands for beta-1 or beta-2 adrenergic receptors. The selectivity of [125I]iodopindolol, [125I]iodocyanopindolol, [125I]iodohydroxybenzylpindolol and [3H]dihydroalprenolol for beta-1 and beta-2 adrenergic receptors was assessed by inhibiting the binding of each radioligand with the beta-1-selective unlabeled ligand ICI 89,406 at increasing concentrations of the radioligand, using membranes prepared from C6 glioma cells, which have both beta-1 and beta-2 adrenergic receptors. Scatchard plots for all four radioligands were linear, with correlation coefficients greater than 0.95. [125I]Iodopindolol and [125I]iodocyanopindolol were 3.2- and 2-fold selective, respectively, and [125I]iodohydroxybenzylpindolol and [3H]dihydroalprenolol were 5.8- and 2.3-fold selective, respectively, for beta-2 adrenergic receptors. Values obtained for the densities of beta-1 and beta-2 adrenergic receptors and the affinities of the receptors for ICI 89,406 were independent of the radioligand used.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Quantitative analysis of the selectivity of radioligands for subtypes of beta adrenergic receptors. 301 23

We studied the regulation of beta-adrenergic receptor (AR) subtypes co-existing in rat C6 glioma cells to clarify the importance of subtype ratio in responses to catecholamines. Radioligand binding studies with [125I]-cyanopindolol showed that beta 1- and beta 2-ARs co-existed in this cell line in approximately an 80:20 ratio. Norepinephrine (NE) and epinephrine (EPI) were equally potent in increasing cAMP accumulation, consistent with a primarily beta 1-response, although both beta 1- and beta 2-components of the response could be isolated using selective agonists (NE and zinterol), and antagonists (CGP 20712A and ICI 118,551). Little or no evidence of beta 3-ARs could be found in this cell line. Treatment of cells with 500 nM dexamethasone (DEX) for 48 hr increased the proportion of beta 2-ARs (20 to 60%). However, a reciprocal decrease in beta 1-ARs resulted in no change in total beta-ARs. Studies on the time-(12 to 72 hr) and concentration- (5 nM to 5000 nM) dependence of DEX treatment showed that increases in beta 2-ARs were closely linked to decreases in beta 1-ARs with little or no change in total receptor density observed at any time or in any concentration studied. Treatment with DEX also increased beta 2- and decreased beta 1-mediated cAMP responses, but did not alter the response to the nonselective agonist, isoproterenol. Northern blot analysis showed a 2- to 3-fold increase in beta 2-AR mRNA, but no change in beta 1-AR mRNA, after exposure to 50 or 500 nM DEX for 48 hr. Surprisingly, after DEX treatment, NE and EPI were still equally potent in activating cAMP accumulation, although responses to the beta 2-selective agonist, zinterol, were increased. These studies show a close reciprocal regulation by DEX of the relative proportions of beta 1- and beta 2-AR subtypes in C6 cells. The functional significance of the changing subtype ratios does not appear to be related to catecholamine responsiveness.
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PMID:Close reciprocal regulation of beta 1- and beta 2-adrenergic receptors by dexamethasone in C6 glioma cells: effects on catecholamine responsiveness. 790 14

We examined the role of beta 1- and beta 2-adrenergic receptor (AR) density and ratio in catecholamine-stimulated cAMP responses in rat C6 glioma cells. These cells, which normally express both subtypes, were stably transfected with an isopropylthio-beta-D-galactoside-inducible vector containing either beta 1AR or beta 2AR coding sequences, and receptor expression was controlled by the time and concentration of isopropylthio-beta-D-galactoside exposure. Induction of the dominant beta 1AR subtype increased the potencies of isoproterenol (ISO) and other agonists in stimulating cAMP accumulation by 20-40-fold without changing maximal response. Induction of beta 2AR expression caused 7-13-fold increases in the potency of ISO, epinephrine, and zinterol, but not of norepinephrine, and a 20-40% loss in maximal response to all agonists. Selective antagonists showed that both subtypes contributed in a nonadditive manner in the response to ISO under different conditions. After beta 2AR induction, the effects of ISO were not blocked by the beta 1-selective antagonist CGP 20712A but were shifted 100-fold to the right by the beta 2-selective antagonist ICI 118,551. However, in the presence of ICI 118,551, CGP 20712A caused an additional 100-fold decrease in ISO potency, and Schild analysis revealed complex interactions between the two subtypes. Each antagonist alone caused smaller shifts to the right in the dose-response curve to NE and, when present simultaneously, completely abolished the NE response. We conclude that beta 1ARs and beta 2ARs have different efficiencies in activating cAMP accumulation in C6 glioma cells. Activation of coexisting subtypes results in complex and sometimes synergistic interactions between the two subtypes, which vary with agonist concentration, selectivity, subtype density, and ratio.
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PMID:Inducible expression of beta 1- and beta 2-adrenergic receptors in rat C6 glioma cells: functional interactions between closely related subtypes. 870 Jan 11

The ability of the delta opioid agonist DPDPE ([D-Pen2, D-Pen4]enkephalin) to stimulate binding of the GTP analog guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) to pertussis toxin-sensitive G proteins has been characterized in membranes from NG108-15 mouse neuroblastoma X rat glioma cells. The presence of GDP, or its hydrolysis-resistant analog GDPbetaS, and Mg++ ions was essential to observe agonist-mediated stimulation of [35S]GTPgammaS binding, although the guanine dinucleotides alone had complex inhibitory and stimulatory effects on [35S]GTPgammaS binding. The relative ability of the delta antagonists benzylidenenaltrexone and naltriben to inhibit DPDPE-stimulated [35S]GTPgammaS binding suggested the opioid receptor involved was of the delta-2 subtype. Ligand binding assays demonstrated biphasic binding of these antagonists to this single receptor type. [35S]GTPgammaS binding was also stimulated by [D-Ser2,Leu5,Thr6]enkephalin > deltorphin II = DPDPE = etorphine > levallorphan = diprenorphine = nalorphine = naltrindole. The delta antagonists benzylidenenaltrexone, TIPP (Tyr-Tic-Phe-Phe) and naltriben had no effect, but ICI 174864 (N, N-diallyl-Tyr-Aib-Phe-Leu-OH) acted as an inverse agonist and inhibited [35S]GTPgammaS binding. Pertussis toxin pretreatment blocked agonist stimulation of [35S]GTPgammaS binding and also reduced basal binding, thus confirming the presence of constitutively active delta receptors. Replacement of Na+ in the assay buffer with K+ afforded an increased level of basal [35S]GTPgammaS binding and an apparent increase in both the inverse agonist activity of ICI 174864 and the agonist activity of the partial agonist diprenorphine relative to the full agonist [D-Ser2, Leu5,Thr6]enkephalin. The stimulation of [35S]GTPgammaS binding to NG108-15 cell membranes allows a functional measure of delta opioid activity that can provide systems of differing relative efficacy.
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PMID:Delta opioid modulation of the binding of guanosine-5'-O-(3-[35S]thio)triphosphate to NG108-15 cell membranes: characterization of agonist and inverse agonist effects. 940 3

1 Maximal stimulant output from the adenylyl cyclase cascade in neuroblastoma x glioma hybrid, NG108-15, cells is limited by the levels of expression of isoforms of adenylyl cyclase. Stable expression in these cells of a constitutively active mutant (CAM) version of the human beta2-adrenoceptor resulted in higher basal adenylyl cyclase activity than following expression of the human wild type beta2-adrenoceptor. Isoprenaline acted as a full agonist in membranes from both wild type and CAM beta2-adrenoceptor expressing clones. 2 Expression of type II adenylyl cyclase resulted in a substantially elevated capacity of isoprenaline to stimulate [3H]-forskolin binding, whereas in CAM beta2-adrenoceptor expressing cells the basal high affinity [3H]-forskolin binding represented a markedly greater % of the maximal effect which could be produced by addition of isoprenaline, and the EC50 for isoprenaline was some 10 fold lower than in cells expressing the wild type beta2-adrenoceptor. 3 Further transfection of the CAM beta2-adrenoceptor expressing cells with type II adenylyl cyclase greatly increased both absolute basal and agonist-stimulated levels of adenylyl cyclase activity. 4 Betaxolol, ICI 118,551, sotalol and timolol acted as inverse agonists with varying degrees of efficacy, whereas propranolol functioned as a neutral antagonist and alprenolol as a partial agonist. 5 Pretreatment of the CAM beta2-adrenoceptor and type II adenylyl cyclase expressing clones with the irreversible alkylating agent BAAM (1 microM) did not reduce the efficacy of isoprenaline but eliminated efficacy from all the inverse agonist ligands. This effect was dependent upon the concentration of BAAM employed, with half-maximal effects being produced between 10 nM and 100 nM of the alkylating agent, which is similar to the concentrations required to prevent subsequent ligand access to some 50% of the CAM beta2-adrenoceptor population. 6 These data demonstrate that inverse agonist efficacy can be modulated by receptor availability and also indicate why in physiological systems, inverse agonism can be difficult to detect.
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PMID:Efficacy of inverse agonists in cells overexpressing a constitutively active beta2-adrenoceptor and type II adenylyl cyclase. 948 23


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