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)

Previous studies of rat cerebral cortex and rat C6 glioma cells have demonstrated that dimeric tubulin is capable of activating the G proteins Gs and Gil via transfer of guanine nucleotide from tubulin to Gs alpha and Gil alpha. To provide further information regarding cytoskeletal modulation of adenylyl cyclase, the present study examined effects of tubulin on the activation of the enzyme in rat striatal membranes. Tubulin, prepared from rat brain by polymerization with the hydrolysis-resistant GTP analog 5'-guanylylimidodiphosphate (GppNHp) caused significant activation of adenylyl cyclase by approximately 130%. Furthermore, tubulin-GppNHp activated SKF 38393-sensitive adenylyl cyclase and potentiated forskolin-stimulated activity of the enzyme. When tubulin, polymerized with the hydrolysis-resistant photoaffinity GTP analog [32p]p3 (4-azidoanilido)-p1-5'-GTP ([32P]AAGTP), was incubated with striatal membranes, AAGTP was transferred from tubulin to Gs alpha as well as Gi alpha with the extents of nucleotide transfers being 7.6 +/- 0.8% and 17.8 +/- 1.4% of AAGTP originally bound to tubulin, respectively. These results indicate that, in rat striatum, the tubulin dimer participates in the stimulatory regulation of adenylyl cyclase by transferring guanine nucleotide to Gs alpha, supporting the hypothesis that tubulin contributes to the regulation of neuronal signal transduction.
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PMID:Tubulin stimulates adenylyl cyclase activity in rat striatal membranes via transfer of guanine nucleotide to Gs protein. 875 Sep 58

Pretreatment of 1321N1 human astrocytoma cells with exogenously added bacterial phospholipase C (PLC) induced an increase in subsequent stimulation of cyclic AMP accumulation by the beta-adrenergic receptor agonist isoproterenol and by the direct adenylyl cyclase activator forskolin, a phenomenon referred to as sensitization. The direct protein kinase C activator phorbol 12-myristate 13-acetate (PMA) induced a similar sensitization. In contrast, in C62B rat glioma cells both PLC and PMA induced a decrease in subsequent cyclic AMP accumulation stimulated by isoproterenol and little or no change in stimulation by forskolin. Although the effects of PMA were completely abolished by pretreating cells overnight with PMA to down-regulate protein kinase C activity, the effects of PLC were inhibited only partially or not inhibited. Pertussis toxin pretreatment did not inhibit the sensitization induced by PLC, whereas sensitization induced by lysophosphatidic acid (previously shown to involve pertussis toxin-sensitive GTP binding proteins) was completely inhibited. Further studies of these phenomena may reveal novel pathways for regulation of the cyclic AMP signalling pathway.
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PMID:Modulation of cyclic AMP accumulation in glial cells by exogenous phospholipase C. 882 10

The cannabinoid receptors expressed in the mouse neuroblastoma X rat glioma NG108-15 cell and the rat pituitary tumor GH4C1 cell were determined by polymerase chain reaction, dideoxysequencing and pharmacologically. The CB1 but not the CB2 or CB1A cannabinoid receptor was found in both cell lines. The cDNA identified in GH4C1 cells corresponds to the rat CB1 receptor. Interestingly, NG108-15 cells express two distinct cDNAs, one corresponds to the rat and the other to the mouse CB1 receptor. The newly developed CB1 receptor selective antagonist SR141716A was found to reverse cannabinoid agonist (WIN55212-2 or CP55940)-induced adenylyl cyclase inhibition. These results provide more direct evidence that the CB1 receptor is mediating the pharmacological actions of cannabinoids in NG108-15 and GH4C1 cells.
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PMID:Determination of the cannabinoid receptors in mouse x rat hybridoma NG108-15 cells and rat GH4C1 cells. 883 54

The mRNA for the 5-hydroxytryptamine receptor 5-HT5A was detected at embryonic day 18 in the rat central nervous system and peaked by postnatal day 20. At all time points examined, 5-HT5A immunoreactivity observed on astrocyte cell bodies and in the stellate processes not only colocalized with the astrocyte-specific marker glial fibrillary acidic protein (GFAP) but was coordinately regulated with GFAP, increasing during development and during gliosis. Transfection of 5-HT5A into glioma cells prevented the 5-HT-induced increase in cAMP observed in untransfected cells and decreased the relative forskolin response by approximately 20%, suggesting that the 5-HT5A receptor couples negatively to adenylyl cyclase in astrocytes. Together, these results indicate a neuron-to-astrocyte serotonergic signaling pathway mediating cAMP concentrations, which could provide a neuronally driven mechanism for regulating astrocyte physiology with relevance to gliosis.
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PMID:The 5HT5A serotonin receptor is expressed predominantly by astrocytes in which it inhibits cAMP accumulation: a mechanism for neuronal suppression of reactive astrocytes. 885 28

1. A series of chain-extended 2-thioether derivatives of adenosine monophosphate were synthesized and tested as agonists for activation of the phospholipase C-linked P2Y-purinoceptor of turkey erythrocyte membranes, the adenylyl cyclase-linked P2Y-purinoceptor of C6 rat glioma cells, and the cloned human P2U-receptor stably expressed in 1321N1 human astrocytoma cells. 2. Although adenosine monophosphate itself was not an agonist in the two P2Y-purinoceptor test systems, eleven different 2-thioether-substituted adenosine monophosphate analogues were full agonists. The most potent of these agonists, 2-hexylthio AMP, exhibited an EC50 value of 0.2 nM for activation of the C6 cell receptor. This potency was 16,000 fold greater than that of ATP and was only 10 fold less than the potency of 2-hexylthio ATP in the same system. 2-hexylthio adenosine was inactive. 3. Monophosphate analogues that were the most potent activators of the C6 cell P2Y-purinoceptor were also the most potent activators of the turkey erythrocyte P2Y-purinoceptor. However, agonists were in general more potent at the C6 cell receptor, and potency differences varied between 10 fold and 300 fold between the two receptors. 4. Although 2-thioether derivatives of adenosine monophosphate were potent P2Y-purinoceptor agonists no effect of these analogues on the human P2U-purinoceptor were observed. 5. These results support the view that a single monophosphate is sufficient and necessary for full agonist activity at P2Y-purinoceptors, and provide insight for strategies for development of novel P2Y-purinoceptor agonists of high potency and selectivity.
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PMID:Identification of potent P2Y-purinoceptor agonists that are derivatives of adenosine 5'-monophosphate. 886 29

Although P2 receptors mediate a myriad of physiological effects of extracellular adenine nucleotides, study of this broad class of receptors has been compromised by a lack of P2 receptor-selective antagonist molecules. The adenine nucleotide-promoted inositol lipid hydrolysis response of turkey erythrocyte membranes, which has been used extensively as a model for P2Y receptors, has been applied to identify molecules that competitively block these receptors. Adenosine-3'-phosphate-5' -phosphosulfate (A3P5PS) promoted activation of phospholipase C that was only 10-25% of that observed with the full P2Y receptor agonists ATP, ADP, and 2-methylthio-ATP (2MeSATP). The small stimulatory effects of A3P5PS were saturable. Moreover, these effects were entirely the result of interaction with the P2Y receptor, because A3P5PS had no effect on activation of phospholipase C through the beta-adrenergic receptor and produced a concentration-dependent inhibition of 2MeSATP-promoted activity over the same range of A3P5PS concentrations that alone caused a small activation of phospholipase C. Increasing concentrations of A3P5PS produced a rightward shift of the concentration-effect curve for 2MeSATP, and Schild transformation of these data revealed that A3P5PS is a competitive P2Y receptor antagonist with a pKB of 6.46 +/- 0.17. The presence of a phosphate in the 2'- or 3'-position appears to be crucial for antagonist activity, because adenosine-3' -phosphate-5'- phosphate (A3P5P) and adenosine-2'- phosphate-5'-phosphate also exhibited competitive antagonist/partial agonist activities. Other 3'-substituted analogues, such as 3'-amino-ATP and 3'-benzoylbenzoyl-ATP, were full agonists with no antagonist activity. A3P5PS, A3P5P, and adenosine-2',5'-diphosphate also were competitive antagonists in studies with the cloned human P2Y1 receptor stably expressed in 1321N1 human astrocytoma cells. Moreover, both A3P5PS and A3P5P were devoid of agonist activity at the human P2Y1 receptor. The effects of these 2'- and 3'-phosphate analogues were specific for the phospholipase C-coupled P2Y1 receptor, because no agonistic or antagonistic effects on the adenylyl cyclase-coupled P2Y receptor of C6 glioma cells or on P2Y2, P2Y4, or P2Y6 receptors stably expressed in 1321N1 human astrocytoma cells were observed. These results describe specific competitive antagonism of the P2Y1 receptor by an adenine nucleotide derivative and provide a potential new avenue for P2 receptor drug development.
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PMID:Identification of competitive antagonists of the P2Y1 receptor. 891 64

Neuroblastoma X glioma hybrid NG108-15 cells were transfected to express stably either the wild-type human beta2-adrenoceptor or a constitutively active mutant (CAM) version of this receptor. Basal adenylyl cyclase activity in cells expressing the CAM beta2-adrenoceptor correlated well with the level of expression of the receptor and was substantially greater than that in cells expressing the wild-type beta2-adrenoceptor. The CAM beta2-adrenoceptor displayed higher affinity for the agonist isoprenaline than the wild-type receptor but not for the antagonist alprenolol or the inverse agonist betaxolol. Pretreatment of cells harboring the CAM beta2-adrenoceptor with betaxolol resulted in a large (4-7-fold within 24 hr) up-regulation in levels of this receptor. This was not observed after exposure of the CAM beta2-adrenoceptor-expressing cells to alprenolol, and a much smaller effect of betaxolol was produced in cells expressing the wild-type receptor. Betaxolol-mediated up-regulation of the CAM beta2-adrenoceptor was both time and concentration dependent. However, this up-regulation did not result in a substantial alteration in the cellular distribution profile of the receptor. Half-maximal up-regulation of the CAM beta2-adrenoceptor required concentrations of betaxolol similar to those needed to cause half-maximal inhibition of basal adenylyl cyclase activity, indicating the receptor up-regulation is associated with the inverse agonist properties of this compound. Despite the large up-regulation of CAM beta2-adrenoceptor levels, treatment with betaxolol did not significantly alter levels of the G protein that couples to this receptor (G(Salpha)). After sustained treatment with betaxolol, Northern analyses did not demonstrate up-regulation of either CAM beta2-adrenoceptor or G(Salpha) mRNA, and up-regulation of the receptor was prevented by cotreatment of the cells with cycloheximide. These data indicate that the up-regulation of the receptor by betaxolol is likely to reflect an increase in translational efficiency of existing mRNA and/or stabilization of the receptor polypeptide from proteolytic degradation and indicate that such effects can be produced by inverse agonists but not by neutral antagonists.
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PMID:Inverse agonist-induced up-regulation of the human beta2-adrenoceptor in transfected neuroblastoma X glioma hybrid cells. 896 68

Alniditan is a new migraine-abortive agent. It is a benzopyran derivative and therefore structurally unrelated to sumatriptan and other indole-derivatives and to ergoline derivatives. The action of sumatriptan is thought to be mediated by 5-hydroxytryptamine (5-HT)1D-type receptors. We investigated the receptor-binding profile in vitro of alniditan compared with sumatriptan and dihydroergotamine for 28 neurotransmitter receptor subtypes, several receptors for peptides and lipid-derived factors, ion channel-binding sites, and monoamine transporters. Alniditan revealed nanomolar affinity for calf substantia nigra 5-HT1D and for cloned h5-HT1D alpha, h5-HT1D beta and h5-HT1A receptors (Ki = 0.8, 0.4, 1.1, and 3.8 nM, respectively). Alniditan was more potent than sumatriptan at 5-HT1D-type and 5-HT1A receptors. Alniditan showed moderate-to-low or no affinity for other investigated receptors; sumatriptan showed additional binding to 5-HT1F receptors. Dihydroergotamine had a much broader profile with high affinity for several 5-HT, adrenergic and dopaminergic receptors. In signal transduction assays using cells expressing recombinant h5-HT1D alpha, h5-HT1D beta, or h5-HT1A receptors, alniditan (like 5-HT) was a full agonist for inhibition of stimulated adenylyl cyclase (IC50 = 1.1, 1.3, and 74 nM, respectively, for alniditan). Therefore, in functional assays, the potency of alniditan was much higher at 5-HT1D receptors than at 5-HT1A receptors. We further compared the properties of [3H]alniditan, as a new radioligand for 5-HT1D-type receptors, with those of [3H]5-HT in membrane preparations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [3H]Alniditan revealed very rapid association and dissociation binding kinetics and showed slightly higher affinity (Kd = 1-2 nM) than [3H]5-HT. We investigated 25 compounds for inhibition of [3H]alniditan and [3H]5-HT binding in the three membrane preparations; Ki values of the radioligands were largely similar, although some subtle differences appeared. Most compounds did not differentiate between 5-HT1D alpha and 5-HT1D beta receptors, except methysergide, ritanserin, ocaperidone, risperidone, and ketanserin, which showed 10-60-fold higher affinity for the 5-HT1D alpha receptor. The Ki values of the compounds obtained with 5-HT1D receptors in calf substantia nigra indicated that these receptors are of the 5-HT1D beta-type. We demonstrated that alniditan is a potent agonist at h5-HT1D alpha and h5-HT1D beta receptors; its properties probably underlie its cranial vasoconstrictive and antimigraine properties.
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PMID:Alniditan, a new 5-hydroxytryptamine1D agonist and migraine-abortive agent: ligand-binding properties of human 5-hydroxytryptamine1D alpha, human 5-hydroxytryptamine1D beta, and calf 5-hydroxytryptamine1D receptors investigated with [3H]5-hydroxytryptamine and [3H]alniditan. 896 79

In neuroblastoma X glioma hybrid, NG1O8-15, cells transfected to stably express a constitutively active mutant (CAM) form of the human beta2-adrenoceptor, the beta-adrenoceptor ligands sotalol and betaxolol functioned as inverse agonists as they reduced basal adenylyl cyclase activity whereas the antagonists dihydroalprenolol and propranolol did not. Maintained presence of the CAMbeta2-adrenoceptor inverse agonists but not the antagonists in the culture medium of the cells resulted in a substantial, concentration-dependent, up-regulation of the CAMbeta2-adrenoceptor. Up-regulation of the CAMbeta2-adrenoceptor by the inverse agonists was prevented by co-incubation of the cells with either propranolol or dihydroalprenolol. Neither maintained elevation of cAMP levels nor the inhibition of adenylyl cyclase activity altered the ability of the inverse agonist ligands to cause receptor up-regulation.
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PMID:Up-regulation of a constitutively active form of the beta2-adrenoceptor by sustained treatment with inverse agonists but not antagonists. 898 Jan 31

The effects of activation of the adenylyl cyclase-protein kinase A pathway on the expression of delta-opioid receptor mRNA in the NG108-15 neuroblastoma x glioma cell line has been investigated. Activation of prostaglandin E1 (PGE1) receptors, which are positively coupled to adenylyl cyclase, resulted in a reduction in delta-receptor messenger RNA levels. Direct stimulation of adenylyl cyclase by forskolin or treatment of cells with the cyclic AMP analogue dibutyryl cyclic AMP (db-cAMP) mimicked the effect of PGE1. Down-regulation in receptor protein levels, as measured by loss of radioligand binding sites, was also observed and its extent correlated well with the decrease in the amount of delta-opioid receptor transcripts. D-Ser2-Leu-enkephalin-Thr6 (DSLET) inhibition of adenylyl cyclase activity was also diminished after db-cAMP treatment. Inhibitors of protein kinase A (PKA) partially reversed the PGE1- and db-cAMP-mediated repression of the delta-opioid receptor mRNA levels. The rate of degradation of delta-opioid receptor mRNA in the presence of actinomycin D was not altered in response to db-cAMP, suggesting that mRNA stability is not reduced by PKA action. The regulation of delta-opioid receptor mRNA levels by db-cAMP was not sensitive to the protein synthesis inhibitor cycloheximide, suggesting that de novo protein synthesis is not required in this process.
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PMID:Regulation of delta-opioid receptor mRNA levels by receptor-mediated and direct activation of the adenylyl cyclase-protein kinase A pathway. 900 47

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