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)

In dissociated cells from chick embryos or from chick limb buds, acetylcholine (ACh) induced an increase in cellular levels of inositol 1,4,5-trisphosphate (Ins-P3) and of inositol 1,3,4,5-tetrakisphosphate (Ins-P4). The concentration of Ins-P3 was enhanced transiently, whereas the level of Ins-P4 remained elevated for at least 20 min after addition of ACh. In most cases the increase in Ins-P4 levels was more pronounced than that of Ins-P3 levels. The inhibition of the ACh-induced inositol-phosphate response by atropine (half-maximal inhibition at 10 nM) indicates the involvement of muscarinic receptors, which in chick embryo cells induce a transient rise and a following persistent elevation of cytosolic Ca2+ activity (G. Oettling et al. (1989) J. Dev. Physiol. 12, 85-94). Adenosine 5'-triphosphate (ATP) elicited a similar transient rise in cytosolic Ca2+ activity, however, without a subsequent plateau. ATP also caused an increase in inositol-oligophosphate levels. Thus, both muscarinic and purinergic receptors in chick embryo cells are coupled to phospholipase C. The enzymatically formed Ins-P3 mediates the release of Ca2+ from internal stores. The Ca2+ signal could be involved in embryonic cell migration during morphogenesis.
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PMID:Chick embryo muscarinic and purinergic receptors activate cytosolic Ca2+ via phosphatidylinositol metabolism. 195 65

Zona fasciculata/reticularis (ZFR) cells, isolated from the bovine adrenal cortex, secreted cortisol in response to acetylcholine (AcCh). The response was present in freshly isolated cells and in cells maintained in primary culture, reaching a maximum after 48-72 h and thereafter declining. Cells maintained in primary culture for 72 h secreted cortisol with an ED50 at 1.2 x 10(-6) M. The potent inhibition of AcCh-stimulated secretion by atropine, and the relative ineffectiveness of nicotine or nicotinic antagonists, were consistent with a predominantly muscarinic response to AcCh in these cells. A selective M1-receptor agonist, McN-A-343, had no effect on cortisol secretion whereas the M3 antagonist, hexahydro-sila-difenidol, produced a dose-dependent inhibition of AcCh-stimulated cortisol secretion. These findings are consistent with AcCh mediating its effects on cortisol secretion through an M3 receptor. While AcCh had no effect on cAMP formation, a dose-dependent increase in [3H]phosphoinositols (identified using high-performance liquid chromatography (HPLC)) occurred in a manner that was not dependent on an influx of extracellular Ca2+. Detailed HPLC analysis of the formation of 3H-labelled phosphoinositols and glycerophosphoinositols from pre-labelled cells over the period 0-15 min showed that the earliest significant rise was in Ins(1,4,5)P3 at 5 s, followed by later rises in InsP1, InsP2 and Ins(1,3,4)P3. Additional studies using cells loaded with fura-2 indicator revealed a 1.6-fold increase in [Ca2+]i from a mean resting value of 75 nM in response to 10(-4) M AcCh. Furthermore, the rise in Ca2+ was not abolished by lowering extracellular Ca2+ to resting cytosolic levels, suggesting the mobilisation of an intracellular pool. These observations indicate that AcCh promotes rapid activation of a Ca2(+)-independent and polyphosphoinositide-specific phospholipase C, and that the Ins(1,4,5)P3 formed releases Ca2+ from an intracellular pool. The stimulation by AcCh of this signal transduction mechanism is consistent with our conclusion, based on the effects of the selective muscarinic agonist and antagonist on cortisol secretion, that the AcCh receptor is of the M3 subtype. We conclude that AcCh, acting through an M3 receptor coupled to phospholipase C, regulates cortisol secretion at the cellular level in bovine adrenal ZFR cells.
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PMID:Acetylcholine stimulates cortisol secretion through the M3 muscarinic receptor linked to a polyphosphoinositide-specific phospholipase C in bovine adrenal fasciculata/reticularis cells. 196 58

The effects of sodium fluoride upon basal and agonist-stimulated inositol phospholipid breakdown have been investigated in rat brain miniprisms. NaF concentration dependently increased basal inositol phospholipid breakdown, with a maximum effect being seen at 20 mM. NaF reduced the inositol phospholipid breakdown responses to stimulation by carbachol, noradrenaline, serotonin and quisqualate, but not to the stimulation produced by raising the assay [K+] from 6 to 18 mM. More detailed study demonstrated NaF to have a 'levelling' effect, reducing all InsP/(Lipid + InsP) values greater than 0.15 (i.e. produced by carbachol at raised [K+], noradrenaline and by 50 mM K+) to about this value. Time-course experiments indicated that NaF treatment reduced the rate of carbachol-stimulated inositol phospholipid breakdown up to this InsP/(Lipid + InsP) level and thereafter blocked further breakdown. Inhibitory effects upon carbachol-stimulated inositol phospholipid breakdown were not seen with forskolin, sodium nitroprusside or 8BrcGMP. Under conditions where there is no de novo synthesis of phosphoinositides from [3H]myo-inositol, NaF reduced the total Lipid + InsP labelling by about 20%. NaF in addition inhibits the activity of Ins(1,4)P2-phosphatase in cerebral cortical homogenates. It is concluded that fluoride ions inhibit agonist-stimulated inositol phospholipid breakdown via actions not only on G-proteins but also on phosphoinositide-specific phospholipase C substrate availability.
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PMID:Multiple actions of fluoride ions upon the phosphoinositide cycle in the rat brain. 196 44

The phospholipase C (PLC)-mediated hydrolysis of membrane phosphoinositides is an important signal transduction pathway coupled to the cell-surface receptors for several hormones and growth factors. In addition, PLC activity can be modulated by changes in intracellular calcium and activation of GTP binding proteins. In this report, differential activation of PLC in the human keratinocyte cell line SCC-12F was studied as judged by specific patterns of inositol phosphate formation. Several hormones and growth factors previously shown to stimulate PLC in a variety of cell types were screened for activity in SCC-12F cells. Only bradykinin was active, stimulating the PLC-dependent generation of inositol (1,4,5) triphosphate (Ins(1,4,5)P3). Ins(1,4,5)P3 was rapidly metabolized to inositol(1,4)biphosphate (Ins(1,4)P2) and inositol(1,3,4,5)tetrakisphosphate (Ins(1,3,4,5)P4), and subsequently degraded to inositol monophosphates. The response elicited by bradykinin was concentration dependent (EC50 value of 50 nM), suggesting involvement of a specific bradykinin receptor. Treatment of these cells with the calcium ionophore A23187 appeared to result in the direct formation of Ins(1,4)P2 without Ins(1,4,5)P3 as precursor. Treatment of the cells with AIF4-, a putative activator of GTP binding proteins, resulted in the generation of inositol monophosphates as the major metabolites in the absence of detectable Ins(1,4,5)P3 formation. Taken together, these observations suggest that the PLC complex present in SCC-12F cells can be differentially activated to yield either Ins(1,4,5)P3, Ins(1,4)P2, or InsP. The observed effects may be due to a direct PLC-dependent hydrolysis of the appropriate membrane phosphoinositide.
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PMID:Inositol phosphate formation in the human squamous cell carcinoma line SCC-12 F: studies with bradykinin, the calcium ionophore A23187, and sodium fluoride. 198 86

The effects of adrenaline on the potential difference across the cell membrane, on formation of inositol phosphates and on intracellular Ca2+ ([Ca2+]i) were analysed in cells without or with pretreatment with pertussis toxin or phorbol 12-myristate 13-acetate (PMA). In untreated cells, adrenaline leads to a sustained hyperpolarization, a stimulation of Ins(1,4,5)P3 and Ins(1,3,4,5,)P4 formation and a transient increase in [Ca2+]i from 78 +/- 7 to 555 +/- 43 nM, followed by a plateau of 260 +/- 23 microM. In the absence of extracellular Ca2+ the effect of adrenaline on both potential difference and [Ca2+]i is transient. In cells pretreated with pertussis toxin, the effects of adrenaline on InsP3 and [Ca2+]i are still preserved, but the effect on potential difference is transient. In cells pretreated with PMA, the effect of adrenaline on InsP3 formation is severely decreased and that on [Ca2+]i abolished, whereas a transient hyperpolarizing effect is still present. This transient hyperpolarization is abolished by additional pretreatment with pertussis toxin. The observations suggest that adrenaline hyperpolarizes the cell membrane of MDCK cells by several distinct mechanisms. First, adrenaline stimulates the formation of InsP3 and InsP4, which at least in part accounts for the release of intracellular Ca2+ and the entry of Ca2+ from the extracellular fluid. Stimulation of phospholipase C is not mediated by pertussis-toxin-sensitive G-proteins, but apparently is inhibited by activation of protein kinase C. Second, adrenaline hyperpolarizes the cell membrane by a mechanism independent from increase in [Ca2+]i which is sensitive to pertussis toxin but is, at least in part, insensitive to PMA.
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PMID:Cellular mechanisms of adrenaline-induced hyperpolarization in renal epitheloid MDCK cells. 200 Dec 40

Pasteurella multocida toxin, both native and recombinant, is an extremely potent mitogen for Swiss 3T3 cells and acts to enhance the formation of total inositol phosphates (Rozengurt, E., Higgins, T., Changer, N., Lax, A.J., and Staddon, J.M. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 123-127). P. multocida toxin also stimulates diacylglycerol production and activates protein kinase C (Staddon, J.M., Chanter, N., Lax, A.J., Higgins, T.E., and Rozengurt, E. (1990) J. Biol. Chem. 265, 11841-11848). Here we analyze, by [3H]inositol labeling and high performance liquid chromatography, the inositol phosphates in recombinant P. multocida toxin-treated cells. Recombinant P. multocida toxin stimulated increases in [3H]inositol 1,4,5-trisphosphate ([3H]Ins(1,4,5)P3) and its metabolic products, including Ins(1,3,4,5)P4, Ins(1,3,4)P3, Ins(1,4)P2, Ins(4/5)P, and Ins(1/3)P. The profile of the increase in the cellular content of these distinct inositol phosphates was very similar to that elicited by bombesin. Furthermore, recombinant P. multocida toxin, like bombesin, mobilizes an intracellular pool of Ca2+. Recombinant P. multocida toxin pretreatment greatly reduces the Ca2(+)-mobilizing action of bombesin, consistent with Ca2+ mobilization from a common pool by the two agents. The enhancement of inositol phosphates and mobilization of Ca2+ by recombinant P. multocida toxin were blocked by the lysosomotrophic agents methylamine, ammonium chloride, and chloroquine and occurred after a dose-dependent lag period. The stimulation of inositol phosphate production by recombinant P. multocida toxin persisted after removal of extracellular toxin, in contrast to the reversibility of the action of bombesin. Recombinant P. multocida toxin, unlike bombesin and guanosine 5'-O-(gamma-thiotriphosphate), did not cause the release of inositol phosphates in permeabilized cells. These data demonstrate that recombinant P. multocida toxin, acting intracellularly, stimulates the phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate.
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PMID:Pasteurella multocida toxin, a potent mitogen, increases inositol 1,4,5-trisphosphate and mobilizes Ca2+ in Swiss 3T3 cells. 200 31

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

In human HeLa carcinoma cells, histamine causes a dose-dependent formation of inositol phosphates, production of diacylglycerol and a transient rise in intracellular [Ca2+]. These responses are completely blocked by the H1-receptor antagonist pyrilamine. In streptolysin-O-permeabilized cells, formation of inositol phosphates by histamine is strongly potentiated by guanosine 5'-[gamma-thio]triphosphate and inhibited by guanosine 5'-[beta-thio]diphosphate, suggesting the involvement of a GTP-binding protein. Histamine stimulates the rapid but transient formation of Ins(1,4,5)P3, Ins(1,3,4)P3 and InsP4. InsP accumulates in a much more persistent manner, lasting for at least 30 min. Studies with streptolysin-O-permeabilized cells indicate that InsP accumulation results from dephosphorylation of Ins(1,4,5)P3, rather than direct hydrolysis of PtdIns. The rise in intracellular [Ca2+] is biphasic, with a very fast release of Ca2+ from intracellular stores, that parallels the Ins(1,4,5)P3 time course, followed by a more prolonged phase of Ca2+ influx. In individual cells, histamine causes a rapid initial hyperpolarization of the plasma membrane, which can be mimicked by microinjected Ins(1,4,5)P3. Histamine-induced hyperpolarization is followed by long-lasting oscillations in membrane potential, apparently owing to periodic activation of Ca2+-dependent K+ channels. These membrane-potential oscillations can be mimicked by microinjection of guanosine 5'-[gamma-thio]triphosphate, but are not observed after microinjection of Ins(1,4,5)P3. We conclude that H1-receptors in HeLa cells activate a PtdInsP2-specific phospholipase C through participation of a specific G-protein, resulting in long-lasting oscillations of cytoplasmic free Ca2+.
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PMID:Histamine-H1-receptor-mediated phosphoinositide hydrolysis, Ca2+ signalling and membrane-potential oscillations in human HeLa carcinoma cells. 215 7

To ascertain whether mannose 6-phosphate-containing peptides that bind to the insulin-like growth factor II (IGF II)/mannose 6-phosphate receptor activate phospholipase C, we determined the effect of proliferin, transforming growth factor-beta 1 (TGF-beta 1) precursor, and beta-galactosidase on production of inositol trisphosphate (Ins-P3) in basolateral membranes isolated from the renal proximal tubule of dogs. Both proliferin and TGF-beta 1 precursor stimulated Ins-P3 production in a concentration-dependent manner. Maximal production was stimulated by approximately 10(-13) M of each peptide. beta-Galactosidase had no effect on Ins-P3 generation. Neither proliferin nor TGF-beta 1 precursor potentiated IGF II-stimulated Ins-P3 production. Mannose 6-phosphate itself had no effect on Ins-P3 generation. However, mannose 6-phosphate potentiated production stimulated by 10(-11) M proliferin or 10(-11) M TGF-beta 1 precursor while inhibiting production stimulated by 10(-14) M of either peptide. Addition of anti-mannose 6-phosphate receptor antibodies to basolateral membranes abolished proliferin and TGF-beta 1 precursor-stimulated Ins-P3 generation. We conclude that, in addition to IGF II, mannose 6-phosphate-containing ligands for the IGF II/mannose 6-phosphate receptor activate basolateral membrane phospholipase C. Such activation could reflect a common mechanism for signal transduction by these peptides mediated via the IGF II/mannose 6-phosphate receptor.
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PMID:Mannose 6-phosphate-containing peptides activate phospholipase C in proximal tubular basolateral membranes from canine kidney. 216 41

LiCl-induced (5 mEq/kg) regional differences in the cerebral phosphoinositide (PI) cycle were studied by measuring inositol-1-phosphate (Ins-1-P), an intermediate in the PI cycle, in male Sprague Dawley and Han/Wistar rats by gas chromatography/mass spectrometry. Control Ins-1-P levels were higher frontally than caudally in both rat strains. LiCl increased Ins-1-P levels 1.8 to 7.4 fold in different regions of brain of Sprague Dawley rats but only 1.2 to 1.8 fold in Han/Wistar rats. This strain difference offers a way to compare the effects of lithium on PI metabolism versus receptor-G protein-phospholipase C coupling mechanisms.
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PMID:Changes in cerebral inositol-1-phosphate concentrations in LiCl-treated rats: regional and strain differences. 216 47


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