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)

1. Previous studies have shown that bovine pulmonary artery endothelium (CPAE) has P2Y and P2U purinoceptors, rat C6 glioma cells have P2U purinoceptors and mouse RAW 264.7 cells have pyrimidinoceptors, all of which are coupled to phosphoinositide-specific phospholipase C (PI-PLC). The dual actions of PPADS, suramin and reactive blue as antagonists of receptor subtypes and ecto-ATPase inhibitors were studied in these three cell types. 2. In CPAE, suramin, at 3-100 microM, competitively inhibited the PI responses induced by 2MeSATP and UTP, with pA2 values of 5.5 +/- 0.3 and 4.4 +/- 0.4, respectively. Reactive blue, at 1-3 microM, produced shifts to the right of the 2MeSATP and UTP curves, but no further right shift at 10 microM. PPADS, at 10 microM, caused a 3 fold right shift of the 2MeSATP curve, but no further shift at concentrations up to 100 microM. In contrast, a dose-dependent shift to the left of the UTP curve and a weak inhibition of the ATP response were seen with PPADS. 3. In RAW 264.7 cells, suramin and reactive blue, but not PPADS, competitively inhibited the UTP response, with pA2 values of 4.8 +/- 0.5 and 5.8 +/- 0.7, respectively. 4. In C6 glioma cells, although suramin and reactive blue inhibited the ATP response, a potentiation effect on ATP and UTP responses was seen with PPADS. 5. The ecto-ATPase inhibitory activity of these three receptor antagonists were determined. All three inhibited ecto-ATPase present in CPAE, C6 and RAW 264.7 cells, with IC50 values of 4, 4.8 and 4.7 for PPADS, 4, 4.4 and > > 4 for suramin, and 4.5, 4.7 and 4.7 for reactive blue. 6. This study indicates that PPADS, suramin and reactive blue ar ecto-ATPase inhibitors. This property, combined with their antagonistic selectivity for receptor subtypes, can result in inhibition of, potentiation of, or lack of effect on agonist-mediated PI responses. Reactive blue is a more potent antagonist than suramin on P2Y, P2U and pyrimidinoceptors, and PPADS is a weak antagonist for P2Y receptors.
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PMID:Inhibition of ecto-ATPase by PPADS, suramin and reactive blue in endothelial cells, C6 glioma cells and RAW 264.7 macrophages. 898 11

1. Four different phospholipase C (PLC)-activating P2Y receptors have been cloned and stably expressed in 1321N1 human astrocytoma cells. These include the human homologues of the P2Y1, P2Y2 and P2Y4 receptors and the rat homologue of the P2Y6 receptor. 2. The nucleotide selectivities of these four receptors have been compared directly by measuring inositol phosphate accumulation in response to nucleotides under conditions in which the initial purity and stability of agonist was rigidly assured and quantitatively assessed. 3. The P2Y1 receptor is specific for adenine nucleotides and slightly more sensitive to disphosphates than triphosphates. When expressed in 1321N1 astrocytoma cells, it couples selectively to the stimulation of PLC and not to the inhibition of adenylyl cyclase. 4. The P2Y2 receptor is activated by UTP and ATP with similar potency and is not activated by nucleoside diphosphates. Diadenosine terraphosphate is a potent agonist at this receptor. 5. The P2Y4 receptor is highly selective for UTP over ATP and is not activated by nucleoside disphosphates. 6. The P2Y6 receptor is activated most potently by UDP, but weakly or not at all by UTP, ADP and ATP. The P2Y6 receptor appears to be identical to the uridine nucleotide-specific receptor previously characterized in C6-2B rat glioma cells. 7. We have identified a P2Y receptor on C6 glioma cells that inhibits adenylyl cyclase but has no effect on PLC. This receptor exhibits a pharmacological selectivity similar but not identical to that of the P2Y1 receptor. When the P2Y1 receptor was expressed in these C6 cells, it conferred an inositol lipid signalling response to adenine nucleotides that was pharmacologically identical to that of the P2Y1 receptor. Thus, the P2Y receptor of C6 glioma cells represents an additional receptor that exhibits the classical pharmacological selectivity of a P2Y1-R, but which couples to adenylyl cyclase rather than to PLC.
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PMID:Pharmacological and second messenger signalling selectivities of cloned P2Y receptors. 913 7

Regulation of inositol phospholipid hydrolysis by UTP and UDP in neuroblastoma x glioma hybrid cell line NG108-15 was potentiated in the presence of ATP. The effect of ATP was dose dependent and shifted the EC50 value for these uracil nucleotides up to three powers of magnitude, having no influence on the maximal value of the response. Adenine nucleotides (ADP, AMP, adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS), beta,gamma-methyleneadenosine 5'-triphosphate (betagammaMeATP), 3'-O-(4-benzoyl)benzoyl ATP (BzATP) and 3'-deoxyadenosine 5'-O-(1-thio)triphosphate (dATPalphaS)) as well as adenosine, had no influence on the pyrimidinoceptor response. The potentiation effect was abolished by excess of EDTA. The results were in agreement with the hypothesis of pyrimidinoceptor affinity regulation via extracellular phosphorylation of the receptor protein, initiated by ATP. This mechanism may have physiological implication for functioning of uracil nucleotides as endogenous signaling molecules.
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PMID:Pyrimidinoceptor potentiation by ATP in NG108-15 cells. 984 88

The ability of UTP, UDP, ATP, and ADP to influence inositol phospholipid hydrolysis in neuroblastoma origin cell lines was assessed. The mouse neuroblastoma lines N1E 115, Neuro 2a, and NB4 1A3 and the rat glioma/mouse neuroblastoma hybrid line NG108-15 gave robust responses to both UTP and UDP, which were essentially equipotent. Thus a range of cell lines of mouse neuroblastoma origin express a pyrimidine-selective P2Y receptor. The NG108-15 cells were the only cell type tested at which ATP and ADP displayed activity with EC50 values of greater than 100 microM, compared with values of 0.58 and 1.25 microM for UTP and UDP, respectively. In contrast to the cell lines derived from mouse neuroblastoma, the human neuroblastoma lines SH-SY5Y and SK-N-SH did not respond to any nucleotides, although both responded well to carbachol.
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PMID:Only pyrimidinoceptors are functionally expressed in mouse neuroblastoma cell lines. 1042 27

1. Extracellular purine and pyrimidine nucleotides have been implicated in the regulation of several cellular functions including mitogenesis. In this study, experiments were conducted to characterize the P2Y receptor on C(6) glioma cells responsible for stimulating cell proliferation associated with mitogen-activated protein kinase (MAPK) activation. 2. UTP and ATP produced a similar effect on [(3)H]-thymidine incorporation in a time- and concentration-dependent manner, suggesting the involvement of P2Y(2) receptor in mediating proliferation of C(6) glioma cells. 3. In response to UTP, both p42 and p44 MAPK were activated in a time- and concentration-dependent manner using Western blot analysis with an anti-phospho-p42/p44 MAPK antibody. The phosphorylation reached maximal levels after 5 min and declining by 30 min. 4. Pretreatment with pertussis toxin (PTX) did not change these responses to UTP. Both DNA synthesis and phosphorylation of MAPK in response to UTP were attenuated by tyrosine kinase inhibitors, genistein and herbimycin A, protein kinase C (PKC) inhibitors, staurosporine and GF109203X, and removal of Ca(2+) by addition of BAPTA/AM plus EGTA. 5. UTP-induced [(3)H]-thymidine incorporation and p42/p44 MAPK phosphorylation was completely inhibited by PD98059 (an inhibitor of MEK1/2). Furthermore, we showed that overexpression of dominant negative mutants of Ras (RasN17) and Raf (Raf-301) completely suppressed MEK1/2 and p42/p44 MAPK activation induced by ATP and UTP. 6. These results conclude that the mitogenic effect of UTP mediated through a P2Y(2) receptor that involves the activation of Ras/Raf/MEK/MAPK pathway. UTP-mediated MAPK activation was modulated by Ca(2+), PKC, and tyrosine kinase associated with cell proliferation in cultured C(6) glioma cells.
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PMID:P2Y(2) receptor-mediated proliferation of C(6) glioma cells via activation of Ras/Raf/MEK/MAPK pathway. 1074 5

1. In glioma C6 cells, the stimulation of P2Y receptors by ADP, ATP and UTP initiated an increase in the intracellular Ca2+ concentration, in a process that involved the release of Ca2+ from InsP(3)-sensitive store and the capacitative, extracellular Ca2+ entry. The presence of external Ca2+ was not necessary to elevate Ca(2+). 2. The rank order of potencies of nucleotide analogues in stimulating [Ca2+](i) was: 2MeSADP > ADP > 2MeSATP = 2ClATP > ATP > UTP. alpha,beta-Methylene ATP, adenosine and AMP were ineffective. 3. ADP and UTP effects were additive, while actions of ATP and UTP were not additive on [Ca2+](i) increase. Similarly, cross-desensitization between ATP and UTP but not between ADP and UTP occurred. 4. Suramin, a non-specific nucleotide receptors inhibitor, antagonized ATP-, UTP- and ADP-evoked Ca2+ responses. PPADS, a selective antagonist of the P2Y(1) receptor-generated InsP(3) accumulation, decreased ADP-initiated Ca2+ response with no effect on ATP and UTP. 5. Pertussis toxin (PTX) reduced ADP- and ATP-induced Ca2+ increases. Short-term treatment with TPA, inhibited both ATP and ADP stimulatory effects on [Ca2+](i). 6. ADP inhibited isoproterenol-induced cyclic AMP accumulation. PTX blocked this effect, but PPADS did not. 7. RT - PCR analysis revealed the molecular identity of P2Y receptors expressed by glioma C6 cells to be both P2Y(1) and P2Y(2). 8. It is concluded that both P2Y(1) and P2Y(2) receptors co-exist in glioma C6 cells. ADP acts as agonist of the first, and ATP and UTP of the second one. Both receptors are linked to phospholipase C (PLC).
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PMID:Two subtypes of G protein-coupled nucleotide receptors, P2Y(1) and P2Y(2) are involved in calcium signalling in glioma C6 cells. 1115 87

In the present study, the P2Y receptor(s) mediating the effects of the pyrimidines UTP and UDP on phospholipase C activation in the mouse neuroblastoma x rat glioma hybrid cell line NG108-15 was investigated. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) analysis detected transcripts for the P2Y(6) and P2Y(2) receptors, but not for P2Y(1) and P2Y(4.) UTP and UDP were equipotent agonists and their effects were partially additive. Suramin, reactive blue 2 and pyridoxal phosphate-6-azophenyl-2',4'disulfonic acid (PPADS) antagonised the phospholipase C response to both UTP and UDP. High micromolar concentrations of adenosine, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680), 2',3'-O-isopropylideneadenosine (iPAdo) and adenosine 3':5'-cyclic monophosphate (3',5'-cAMP) were able to antagonise the effect of UTP on phospholipase C but not that of UDP. The additivity of the UTP and UDP responses, novel P2 receptor antagonist profile and the distinguishing action of adenosine may indicate the expression of a pyrimidine selective P2Y receptor in addition to the P2Y(6) type in these cells.
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PMID:Pharmacological characterisation of pyrimidinoceptor responses in NG108-15 cells. 1127 90

1. Extracellularly added P(1),P(3)-di(adenosine-5') triphosphate (Ap(3)A), P(1),P(4)-di(adenosine-5') tetraphosphate (Ap(4)A), ATP, ADP, AMP and adenosine are growth inhibitory for rat C6 glioma cells. Analysis of nucleotide hydrolysis and the use of nucleotidase inhibitors demonstrated that the latter inhibition is due to hydrolysis of the nucleotides to adenosine. 2. Agonists of the P2Y(AC)(-)-receptor enhance the growth of C6 cells if their hydrolysis to adenosine is inhibited by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). In these conditions, the potency to stimulate cell growth parallels the ranking of the receptor agonists, i.e. 2-methylthioadenosine-5'-diphosphate (2MeSADP)>Ap(3)A>Ap(4)A. ATP and ADP are still hydrolysed in the presence of PPADS and have no proliferative effect on C6 cells. 3. The enhanced growth is due to a P2Y(AC)(-)-receptor-mediated activation of p42/44 mitogen-activated protein kinase (MAPK) as shown by immunoblotting and protein kinase assays for active MAPK and the use of the MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059. 4. The UTP-induced enhancement of the growth of C6 cells is due to activation of MAPK by a PPADS sensitive nucleotide receptor. 5. In conclusion, the effect of nucleotides on the growth of C6 cells is determined by ecto-nucleotidases and by activation of nucleotide receptors. Hydrolysis of nucleotides to adenosine induces growth inhibition while inhibition of the hydrolysis of agonists of the P2Y(AC)(-)-receptor enhances cell growth by activation of MAPK.
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PMID:P2Y(AC)(-)-receptor agonists enhance the proliferation of rat C6 glioma cells through activation of the p42/44 mitogen-activated protein kinase. 1156 59

An easy and fast method for the quantitative analysis of nucleotides by capillary zone electrophoresis was developed. The method employing a neutral-bonded capillary and reversed polarity mode provided a good resolution and a short analysis time of less than 5 min. The samples were injected electrokinetically using -6 kV voltage for 30 s and detected by their UV absorbance at 254 nm. Constant current (-45 microA) was applied, and a phosphate buffer, pH 7.4, was used. The detection limits for ATP, UDP, and UTP ranged between 0.14 and 0.28 microM. This method was required for the investigation of the purity of the commercially available nucleotides used in pharmacological studies. In addition, the analytical method was applied to study the metabolism of nucleotides in a cell line, neuroblastoma x glioma hybrid cells (NG108-15), which is used in pharmacological studies with nucleotides, since it contains purine- and pyrimidine-sensitive nucleotide receptors. Furthermore, we used the new method for monitoring enzymatic studies using the enzyme hexokinase to convert nucleotide triphosphates to diphosphates.
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PMID:Fast, efficient capillary electrophoresis method for measuring nucleotide degradation and metabolism. 1206 39

The effects of actin cytoskeleton disruption by cytochalasin D and latrunculin A on Ca2+ signals evoked by ADP, UTP or thapsigargin were investigated in glioma C6 cells. Despite the profound alterations of the actin cytoskeleton architecture and cell morphology, ADP and UTP still produced cytosolic calcium elevation in this cell line. However, calcium mobilization from internal stores and Ca2+ influx through store-operated Ca2+ channels induced by ADP and UTP were strongly reduced. Cytochalasin D and latrunculin A also diminished extracellular Ca2+ influx in unstimulated glioma C6 cells previously incubated in Ca2+ free buffer. In contrast, the disruption of the actin cytoskeleton had no effect on thapsigargin-induced Ca2+ influx in this cell line. Both agonist- and thapsigargin-generated Ca2+ entry was significantly decreased by the blocker of store-operated Ca2+ channels, 2-aminoethoxydiphenylborate. The data reveal that two agonists and thapsigargin activate store-operated Ca2+ channels but the mechanism of activation seems to be different. While the agonists evoke a store-mediated Ca2+ entry that is dependent on the actin cytoskeleton, thapsigargin apparently activates an additional mechanism, which is independent of the disruption of the cytoskeleton.
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PMID:Role of the actin cytoskeleton in store-mediated calcium entry in glioma C6 cells. 1216 45


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