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: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The signal transduction of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2), cyclooxygenase products of arachidonic acid, was investigated in smooth muscle preparations and 1321N1 human astrocytoma cells. While PGE2 has been known to stimulate (via EP2 receptor) or inhibit (via EP3 receptor) adenylate cyclase, PGE2 activated phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phospholipase C (PLase C) in non-vascular smooth muscles (via EP1 receptor), resulting in accumulations of inositol trisphosphate (IP3) and diacylglycerol to elicit intracellular Ca2+ mobilization. On the other hand, STA2, a TXA2 receptor analogue, also accumulated IP3 in human astrocytoma cells. [3H]SQ 29548, a TXA2 receptor antagonist, specifically bound to astrocytoma membranes. TXA2-receptor antagonists (ONO NT-126, S-145, SQ29548 and ONO3708) concentration-dependently inhibited PIP2-specific PLase C activation by STA2, and they also inhibited [3H]SQ 29548 binding in human astrocytoma cells. The Ki value of each antagonist in PIP2-specific PLase C inhibition was similar to that in [3H]SQ29548 binding inhibition. In membrane preparations, STA2 activated PIP2-specific PLase C in the presence of GTP gamma S. Pertussis toxin (IAP) did not affect STA2-induced PLase C activation. The results suggest that stimulation of TXA2 receptors activates PIP2-specific PLase C via an IAP-insensitive G-protein.
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PMID:[Signal transduction of prostaglandin E2 and thromboxane A2]. 131 76

We have examined the activation of a phospholipase C signal transduction pathway by a B2-bradykinin receptor in the human astrocytoma cell line D384 and how this influences D1-dopamine receptor stimulated cyclic AMP accumulation. Addition of bradykinin to D384 cells resulted in a concentration-dependent (10(-11)-10(-6) M) increase in the accumulation of [3H]inositol phosphates and a similar concentration-dependent transient increase in specific [3H]beta-phorbol-12,13-dibutyrate binding which is indicative of translocation of protein kinase C from the cytosol to the membrane. Changes in intracellular Ca2+ of single cells, measured using the fluorescent indicator dye fura-2, indicated that bradykinin produced a rapid, but transient, increase in intracellular calcium. The Ca2+ response was largely independent of extracellular Ca2+ supporting the idea that receptor activation leads to mobilization of Ca2+ from intracellular stores. However, extracellular Ca2+ was required for a response to a rechallenge with bradykinin. The bradykinin B2-receptor agonist kallidin increased cytosolic Ca2+ in a similar manner to bradykinin. The Ca2+ response to bradykinin could be partially reduced in the presence of the B2-receptor antagonist [D-Arg0-Hyp,D-Phe7,beta-(2-Thienyl)-Ala5,8]-bradykinin, whereas the B1-receptor agonists (Des-Arg9]-bradykinin and [Des-Arg10]-kallidin were ineffective. Bradykinin was also found to attenuate dopamine stimulated cyclic AMP accumulation in D384 cells, at similar concentrations previously observed to stimulate the phospholipase C signal transduction pathway, in the presence of the phosphodiesterase inhibitor, rolipram. In contrast, no attenuation was observed in the presence of the phosphodiesterase inhibitor 1-isobutyl 3-methylxanthine, although the level of dopamine stimulated cyclic AMP observed was lower than in the presence of rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of a B2-bradykinin receptor linked to phospholipase C and inhibition of dopamine stimulated cyclic AMP accumulation in the human astrocytoma cell line D384. 132 96

The effect of adenosine on phosphoinositide hydrolysis was examined in 1321N1 human astrocytoma cells. Adenosine, L-N6-phenylisopropyladenosine (L-PIA), and 5'-(N-ethylcarboxamido)adenosine (NECA) inhibited histamine-stimulated accumulation of inositol phosphates in a concentration-dependent manner. The potency order of adenosine analogues for inhibition of inositol phosphate accumulation was L-PIA greater than adenosine greater than NECA, a finding indicating that A1-class adenosine receptors are involved in the inhibition. The reduction in inositol phosphate accumulation by L-PIA was blocked by an adenosine receptor antagonist, 8-phenyltheophylline. Stimulation of A1-class adenosine receptors inhibited isoproterenol-stimulated cyclic AMP accumulation as well as histamine-induced inositol phosphate accumulation. Both inhibitory effects were blocked by pretreatment of the cells with pertussis toxin [islet-activating protein (IAP)]. L-PIA also inhibited guanosine 5'-(gamma-thio)triphosphate (GTP gamma S)-stimulated accumulation of inositol phosphates in membrane preparations, and 8-phenyl-theophylline antagonized the inhibition. L-PIA could not inhibit GTP gamma S-induced accumulation of inositol phosphates in IAP-treated membranes. Gi/Go, purified from rabbit brain, inhibited GTP gamma S-stimulated accumulation of inositol phosphates in a concentration-dependent manner in membrane preparations. These results suggest that stimulation of A1-class adenosine receptors interacts with the IAP-sensitive G protein(s), resulting in the inhibitions of phospholipase C as well as adenylate cyclase in human astrocytoma cells.
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PMID:Adenosine inhibits histamine-induced phosphoinositide hydrolysis mediated via pertussis toxin-sensitive G protein in human astrocytoma cells. 165 Mar 98

The ability of angiotensin peptides to stimulate prostaglandin release and raise intracellular calcium levels by activating a phosphoinositide-specific phospholipase C was assessed in three human astrocytoma cell lines (CRTG3, STTG1, and WITG2). The addition of angiotensin II to CRTG3 cells resulted in a dose-dependent release of prostaglandin E2 and prostacyclin, the production of inositol 1,4,5-trisphosphate, and the mobilization of intracellular calcium. Angiotensin-(1-7), previously considered to be an inactive metabolite of angiotensin II, was as potent as angiotensin II for prostaglandin release but did not activate phospholipase C or mobilize intracellular calcium. In contrast, angiotensin-(2-8) caused only a slight increase in prostaglandin release, even though it was as effective as angiotensin II in augmenting inositol 1,4,5-trisphosphate production and calcium mobilization. Moreover, neither the release of prostaglandins in response to angiotensin II or angiotensin-(1-7) nor the mobilization of intracellular calcium in response to angiotensin II required extracellular calcium. Angiotensin II and angiotensin-(1-7) caused the release of prostaglandins from all three human astrocytoma cell lines, but changes in the level of intracellular calcium in response to angiotensin II only occurred in CRTG3 cells. Although previous studies have provided evidence for angiotensin receptor subtypes on the basis of selectivity of antagonists or signal transduction mechanisms, these data suggest that human astrocytes contain multiple angiotensin receptor subtypes on the basis of their response to different angiotensin heptapeptides--angiotensin-(1-7) and angiotensin-(2-8).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human astrocytes contain two distinct angiotensin receptor subtypes. 186 Jul 9

Stimulation of thromboxane A2 (TXA2) receptors in human astrocytoma cells (1321N1) results in activation of phospholipase C via a pertussis toxin-insensitive G-protein. In the present study, the potency of a new TXA2 receptor antagonist, ONO NT-126, was examined with regard to receptor binding and phosphoinositide hydrolysis in human astrocytoma cells and was compared to that of the other known TXA2 antagonists. [3H]SQ29548 binding to membranes was inhibited by ONO NT-126 and the other TXA2 antagonists with Ki values (nM) of 0.09, 2.18, 8.35 and 25.9 for ONO NT-126, S-145, SQ29548 and ONO3708, respectively. STA2 and U46619, TXA2 receptor agonists, also inhibited [3H]SQ29548 binding with Ki (nM) of 25.1 and 233.5, respectively. STA2 and U46619 stimulated phosphoinositide hydrolysis in a concentration-dependent manner with EC50 values of 43.6 nM for STA2 and 1.2 microM for U46619, respectively. STA2 (1 microM)-induced phosphoinositide hydrolysis was also inhibited by TXA2 antagonists. The Ki values of TXA2 antagonists for the inhibition of phosphoinositide hydrolysis (nM) were 0.10 for ONO NT-126, 3.31 for S-145, 8.31 for SQ29548 and 19.49 for ONO3708 all of which were similar to those for receptor binding. The results indicate that ONO NT-126 is a potent and selective antagonist of TXA2 receptors in human astrocytoma cells.
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PMID:ONO NT-126 is a potent and selective thromboxane A2 antagonist in human astrocytoma cells. 196 27

Different membrane-associated isoforms of the neural cell adhesion molecules have been described. One of them, N-CAM120, has been shown to be anchored to the membranes by a complex glycan-phosphatidylinositol group and to be releasable, under soluble form, by the bacterial enzyme phosphatidylinositol-phospholipase C. We used the C6 rat astrocytoma cell line expressing both N-CAM120 and the transmembrane isoform N-CAM140 as a model system. We investigated whether artificial depletion of cell membrane N-CAM120 influences the synthesis and the messenger RNA transcript levels of the isoforms of the neural cell adhesion molecules. Our results showed an increase in the rate of N-CAM120 protein synthesis, whereas the expression of N-CAM140 decreased. Additionally, perturbations in the levels of the 6.7-kb messenger RNA encoding for N-CAM140 were observed, whereas the 2.7-kb transcript encoding for N-CAM120 remained stable. Examination of the time course for the reexpression of N-CAM120 showed that control levels were recovered after 24 h. We provide evidence that N-CAM120 spontaneously released in the culture medium is not incorporated into the extracellular matrix; however, its concentration is important because, if the medium was changed, cells rapidly released a new pool.
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PMID:Removal of C6 astrocytoma cell surface molecules with phosphatidylinositol phospholipase C: effect on regulation of neural cell adhesion molecule isoforms. 205 Nov 73

We have used the 1321N1 astrocytoma cell as a model system for understanding the molecular events involved in signal transduction through phospholipid metabolism. This clonal cell line expresses muscarinic cholinergic receptors (mAChR) that interact with a GTP-binding protein to regulate phospholipase C, rapidly increasing Ins 1,4,5-P3 and mobilizing intracellular Ca2+. Diacylglycerol (DAG) is also increased following mAChR stimulation but the increase in DAG is not significant until several minutes after addition of the mAChR agonist carbachol. To determine the role of Ca2+ and DAG in the activation of protein kinase C (PKC), we assessed PKC redistribution in the intact cell by measuring membrane-associated [3H]phorbol dibutyrate ([3H]PDB) binding. mAChR activation leads to a two-fold increase in [3H]PDB binding which is rapid, transient and temporally correlated with the increase in cytosolic [Ca2+]. When the rise in cytosolic [Ca2+] is buffered with Quin-2 or BAPTA the increase in [3H]PDB binding is inhibited. Studies using subtype-specific antibodies to PKC reveal only the alpha-subtype and confirm that mAChR stimulation causes redistribution of PKC immunoreactivity to a particulate cell fraction only when Ca2+ is increased. Our data suggest that the relatively slow increase in DAG is not the trigger for PKC redistribution and may be secondary to the activation of PKC. Thus, when 1321N1 cells are stimulated with phorbol 12-myristate 13-acetate (PMA) to activate PKC there is a rise in the cellular DAG content. In addition, in cells treated with PMA to down-regulate PKC, carbachol no longer significantly increases DAG mass. These data suggest that PKC is a mediator in the generation of DAG. Analysis of the fatty acid composition of the DAG formed in response to mAChR stimulation suggests that it is mostly derived from phosphatidylcholine (PC) rather than from inositol phospholipids. We examined the effect of mAChR stimulation on PC metabolism in 1321N1 cells. Cells were labelled with [3H]choline which was incorporated into PC and released into the medium when the cells were stimulated with carbachol or with PMA. [3H]Choline release increased throughout a 20-min stimulation. PKC down-regulation abolished both PMA and carbachol-stimulated [3H]choline release. These data support the hypothesis that mAChR stimulation leads to phospholipase D-mediated PC hydrolysis through activation of PKC. Activation of phospholipase D (PLD) was demonstrated by the finding that phosphatidic acid increased in response to PMA or carbachol prior to the increase in PA. In addition, phosphatidylethanol was formed in response to PMA and carbachol in cells exposed to ethanol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Muscarinic receptor regulation of protein kinase C distribution and phosphatidylcholine hydrolysis. 213 May 11

Mastoparan inhibited [3H]inositol phosphate accumulation induced by carbachol as well as cyclic AMP accumulation induced by isoproterenol in 1321N1 human astrocytoma cells. Mastoparan inhibited GTP gamma S-induced, but not Ca2(+)-induced, [3H]inositol phosphate accumulation in membrane preparations with an IC50 of approximately 10 microM. The inhibitory effect of mastoparan on carbachol-induced [3H]inositol phosphate accumulation was resistant to pertussis toxin (IAP) treatment in intact cells. These results suggest that mastoparan inhibits phospholipase C in human astrocytoma cells via a GTP binding protein, which is not a substrate for IAP.
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PMID:Mastoparan inhibits phosphoinositide hydrolysis via pertussis toxin-insensitive [corrected] G-protein in human astrocytoma cells. 215 79

PGJ2 and delta 12PGJ2 (1 microM to 30 microM) inhibited the growth of human astrocytoma cells (1321N1) in a time-dependent manner within 48 hrs, determined by [3H]thymidine incorporation into acid-insoluble fraction or amounts of protein. The EC50 values for PGJ2 and delta 12PGJ2 were approximately 8 microM and 6 microM, respectively. [3H]Thymidine incorporation to acid insoluble fraction was inhibited by these PGs within 1 hr, indicating that these PGs rapidly affect cell functions. Although it has been reported that an increase in cyclic AMP inhibits cell growth, PGJ2 and delta 12PGJ2, but not PGE1, reduced isoproterenol (10 microM)-induced accumulation of cyclic AMP, suggesting that PGJ2 and delta 12PGJ2 may disturb adenylate cyclase system, which might be independent on cell growth. On the other hand, these PGs inhibited the incorporation of [3H]inositol into phospholipid fraction within 6 hrs. Furthermore, PGJ2 and delta 12PGJ2 inhibited carbachol- and/or histamine-induced accumulation of inositol phosphates with a similar dose-dependency to their inhibitions of cell growth. In membrane preparations, however, PGJ2 and delta 12PGJ2 failed to inhibit GTP gamma S (10 microM)- nor Ca2+ (1 mM)-induced accumulation of inositol phosphates. The site of PGJ2 or delta 12PGJ2 in inhibition of inositol phosphate accumulation would not be phospholipase C nor a putative GTP binding protein involved in activation of phospholipase C. The present results indicate that PGJ2 and delta 12PGJ2 inhibit cell growth in human astrocytoma cells and the inhibition of phosphoinositide turnover by these PGs might be involved in the inhibition of cell growth.
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PMID:PGJ2 and delta 12PGJ2 inhibit cell growth accompanied with inhibition of phosphoinositide turnover in human astrocytoma cells. 217 1

BALC/c mice were immunized with isolated human brain Thy-1. The antisera at an appropriate dilution only reacted with a doublet of an apparent molecular weight (MW) around 25,000 among all the glycoproteins of brain tissue isolated by lentil lectin affinity chromatography when tested by enzyme-linked immunosorbent assay and immunoblotting. When the antisera were used to test a number of human cell lines and a marmoset T-cell line (70N2) by flow cytometry, an astrocytoma cell line (U-373), a T-lymphoblastoid cell line (MOLT-3), and two cutaneous T-lymphoma cell lines (HUT-78 and HUT-102) as well as the 70N2 cells were stained. However, a B-lymphoma cell line (Raji), a plasmacytoma cell line (HMy2), and normal peripheral blood lymphocytes were negative. When the positive cells were treated with phosphatidylinositol-specific phospholipase C, a significant decrease in both stain intensity and percentage of positive cells was demonstrated by immunofluorescence. Although Thy-1 expression in human lymphoid system is currently thought to be confined in early T- and B-lymphocyte development, our data suggest that well-differentiated T cells with mature phenotypes such as HUT-78 and HUT-102 which may be considered as tumor counterparts are also capable of expressing Thy-1, presumably after certain stimulation.
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PMID:Expression of Thy-1 and effect of phosphatidylinositol-specific phospholipase C on primate and murine cell lines. 245 68


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