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 effects of sulphasalazine on the production of second messenger compounds in human granulocytes have been characterised by various stimuli. The increases in cytosolic calcium, inositol trisphosphate, diacylglycerol, and phosphatidic acid (all important mediators of intracellular signal transduction) triggered by stimulation were inhibited by sulphasalazine. The metabolites 5-amino-salicylic acid and sulphapyridine were less potent inhibitors than the mother compound. It is concluded that sulphasalazine inhibits the synthesis of phosphoinositide derived second messenger compounds at the level of phospholipase C or its regulatory guanosine 5'-triphosphate (GTP) binding protein. Inhibition of phosphatidic acid synthesis was either due to the same mechanism, or to interaction with a phospholipase D regulating GTP binding protein.
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PMID:Sulphasalazine inhibition of human granulocyte activation by inhibition of second messenger compounds. 136 17

In the last decade a great deal of attention was awarded to a signal transduction pathway which is utilized primarily by 'Ca2+ mobilizing' signal molecules and which involves the hydrolysis of a quantitatively minor phospholipid, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) by a PtdIns-specific phospholipase C (PLC). The evidence for the existence of receptor-mediated GTP binding protein-coupled PLC in myocardium and its possible functions are briefly summarized. The minireview is concentrated on the following aspects: 1) cellular localization and synthesis of polyphospho-PtdIns from PtdIns, 2) desensitization of the alpha 1-adrenergic agonist and endothelin-1 mediated PtdIns responses, 3) oscillatory Ca2+ transients initiated by PtdIns(4,5)P2 hydrolysis, 4) polyunsaturated fatty acids as constituents of polyphospho-PtdIns and of the protein kinase C activator 1,2-diacylglycerol (DAG), 5) source other than PtdIns(4,5)P2 contributing to the stimulated DAG, 6) role of the PtdIns pathway in cardiomyocyte growth and gene expression during the hypertrophic response.
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PMID:Occurrence and functions of the phosphatidylinositol cycle in the myocardium. 136 47

FRTL-5 thyroid cells express a muscarinic receptor which inhibits the phospholipase C activity in a pirenzepine-insensitive manner. We here report that the cholinergic agonist carbachol decreases in these cells the steady-state iodide content, an effect correlated with the iodination of thyroglobulin and with thyroid hormone formation. Several signal pathways may be involved in this phenomenon since carbachol in addition to inhibiting phospholipase C, increased the arachidonic acid release and modified the adenylyl cyclase activity. In FRTL-5 cells, arachidonic acid is released via the direct stimulation of phospholipase A2 by a pirenzepine-sensitive muscarinic receptor coupled to a GTP binding protein sensitive to pertussis toxin. Regarding adenylyl cyclase, carbachol potentiated the thyrotropin-induced stimulation of the enzyme, whereas it did not affect the basal levels of cAMP. In vitro binding studies revealed the presence of two muscarinic binding sites. To summarize, the analysis of signal pathways and of in vitro binding sites indicates a complex muscarinic regulation of thyroid function, which includes the modulation of iodide fluxes.
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PMID:Muscarinic regulation of phospholipase A2 and iodide fluxes in FRTL-5 thyroid cells. 165 22

The mechanisms whereby adenosine-5'-triphosphate (ATP) regulates the inositol phospholipid-signalling system were studied in rat hepatocytes. Intact hepatocytes respond to extracellular ATP, adenosine-5'-O-(3-thiotriphosphate) (ATP gamma S), ADP and weakly to guanosine-5'-triphosphate (GTP), but not to other purine nucleotides (GDP or AMP). This is consistent with the idea that a P2 purinergic receptor is coupled to the phosphatidylinositol metabolism in these cells. Partially purified plasma membranes prepared from myo-[3H]inositol prelabelled hepatocytes exhibit a phosphatidylinositol-4,5-bisphosphate phospholipase C activity sensitive to ATP, ATP gamma S and guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S). Moreover the GTP gamma S effect is greatly enhanced by ATP and ATP gamma S. These potentiating effects differ according to the adenylnucleotide considered. ATP produces (1) an increase in the GTP gamma S-PLC sensitivity, (2) a potentiation of the phospholipase C (PLC) response induced by maximal dose of GTP gamma S, and (3) an increase in the inositol lipids pools. At variance, ATP gamma S, a nonhydrolysable analogue of ATP, only increases the PLC-sensitivity towards GTP gamma S. These results may signify that ATP stimulates inositol phosphate accumulation via at least two distinct mechanisms (i) a direct activation of a P2 purinergic receptor coupled to a PLC via a GTP binding protein and (ii) a stimulation of the phosphatidylinositol (PI) and phosphatidylinositol-4-phosphate (PIP) kinases which increased the pool of phospholipase C substrates.
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PMID:Dual effects of ATP on phosphatidylinositol breakdown in rat hepatocyte membranes. 166 38

Changes in the intracellular free calcium ([Ca2+]i) of cultured normal human epidermal keratinocytes (NHEK) were investigated in order to determine whether the adenylate cyclase cAMP (AC) system and phospholipase C activating system are involved in increasing [Ca2+]i. NHEK were obtained from neonatal foreskin and grown in serum-free medium (K-GM) supplemented with 2% bovine pituitary extract. [Ca2+]i was measured by fluorescence ratio imaging microscopy using Fura-2 as the indicator. In the case of the AC system, transient increases in [Ca2+]i were observed in response to stimulation with epinephrine, norepinephrine, isoproterenol and salbutamol. Methoxamine, clonidine and dobutamine did not induce any [Ca2+]i increase. The [Ca2+]i increase evoked by epinephrine was inhibited by pretreatment with propranolol, but not by prazosin or yohimbine, indicating that epinephrine-induced [Ca2+]i elevation via beta 2-adrenergic stimulation. Similar changes were observed when NHEK were stimulated with histamine, adenosine, GTP gamma S, forskolin and dibutyryl cAMP respectively. The absence of extracellular Ca2+ had no effect on the epinephrine-induced [Ca2+]i increase. It appears that activated protein kinase A, based on cAMP accumulation via stimulatory GTP binding protein, elicited the release of Ca2+ from intracellular stores. On the other hand, when drugs known to activate phospholipase C in a wide variety of cell types were tested, a transient increase in [Ca2+]i was demonstrated in response to the addition of thrombin, bradykinin and substance P. This reaction was not affected by the presence of EGTA, suggesting that these drugs raise [Ca2+]i via phosphatidylinositol breakdown. Vasopressin, angiotensin II, serotonin and acetylcholine did not induce any increase in [Ca2+]i. On the basis of these studies, it was concluded that NHEK possess the mechanism which increase [Ca2+]i via AC system and phospholipase C activating system. It seems probable that this rise in [Ca2+]i initiates a calcium-dependent cellular response, such as activation of calcium/calmodulin dependent kinase, and subsequently regulates the proliferation and differentiation of human epidermal keratinocytes.
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PMID:[Changes in the intracellular free calcium of cultured human epidermal keratinocytes]. 171 97

We have studied the possible involvement of the GTP-binding protein (G-protein) in the activation of phospholipase C and A2 in cultured rat luteal cells as a transducer of cell information. 1. Inositol phosphate production and arachidonic acid release in rat luteal cells by the stimulation of PGF2 alpha and GnRH receptors are dependent on GTP and therefore suggest the involvement of GTP binding protein. 2. When the cells were not treated with IAP, a membrane protein of 41K molecular weight was apparently labeled. The protein, with a molecular weight of 41K, which was obtained from cultured rat luteal cells without prior treatment with IAP is considered to be the alpha-subunit of GTP binding protein as reported in other cells. While alpha-subunit of G-protein was ADP-ribosylated in luteal cells too, the 41K protein from the cells pretreated with IAP was not found to be ADP ribosylated. 3. When such IAP pretreated luteal cells were stimulated by PGF2 alpha or GnRHa, the production of inositol phosphate and the release of arachidonic acid were observed with no suppression. 4. The results suggest the existence of some G-protein other than Gi between the receptor and phospholipases C and A2.
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PMID:[A study on GTP-binding protein in the activation of phospholipase C and phospholipase A2 in cultured rat luteal cells]. 190 81

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

Phosphatidylinositol 4-phosphate (PIP) kinase (E.C. 2.7.1.68) has been purified about 1200-fold from rat liver plasma membranes, taking advantage of affinity chromatography on quercetin-Sepharose as a novel step. The purified PIP kinase showed no contamination by the following enzyme activities: phosphatidylinositol (PI) kinase (EC 2.7.1.67), protein kinase C (EC 2.7.1.-), diacylglycerol kinase (EC 2.7.1.-), phospholipase C (EC 3.1.4.11), protein-tyrosine kinase (EC 2.7.1.112), alkaline phosphatase (EC 3.1.3.1), triphosphoinositide phosphomonoesterase (EC 3.1.3.36), adenylate kinase (EC 2.7.4.3) and cAMP-dependent protein kinase (EC 2.7.1.37). The liver membrane enzyme requires high Mg2+ concentrations with a KM value of 10 mM. Ca2+ or Mn2+ could replace Mg2+ to a certain, though small, extent. Apparent KM values with respect to PIP and ATP were 10 and 65 microM, respectively. GTP was slightly utilized by the kinase as phosphate donor while CTP was not. Quercetin inhibited the enzyme with Ki = 34 microM. Extending our previous observations (Urumow, T. and Wieland, O.H. (1986) FEBS Lett. 207, 253-257 and Urumow, T. and Wieland, O.H. (1988) Biochim. Biophys. Acta 972, 232-238) [gamma S]pppG still stimulated the PIP kinase in extracts of solubilized liver membranes. 20-40% (NH4)2SO4 precipitation of the membrane extracts yielded a fraction that contained the bulk of enzyme activity but did not respond to stimulation by [gamma S]pppG any longer. This was restored by recombination with a protein fraction collected at 40-70% (NH4)2SO4 saturation, presumably containing a GTP binding protein and/or some other factor separated from the PIP kinase. In the reconstituted system [gamma S]pppG stimulated PIP kinase in a concentration dependent manner with maximal activation at 5 microM. This effect was not mimicked by [gamma S]pppA and was blocked by [beta S]ppG. These results strongly support our view that in liver membranes PIP kinase is regulated by a G-protein.
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PMID:Purification and partial characterization of phosphatidylinositol-4-phosphate kinase from rat liver plasma membranes. Further evidence for a stimulatory G-protein. 215 97

The human CSF-1 receptor (c-fms protooncogene product) was introduced into CSF-1-unresponsive Chinese hamster lung fibroblasts (CCL39 cell line) in order to study its coupling to biochemical signal-transducing systems and to compare the growth-regulating properties of CSF-1 to those of other growth factors. Independent clones expressing different levels of CSF-1 receptors were isolated and characterized. CSF-1 increased [3H]thymidine incorporation in serum-starved cells and potentiated the mitogenic effects of FGF and thrombin. As already observed for other growth factors activating receptor tyrosine kinases (EGF, FGF, IGF-I), CSF-1 alone did not trigger inositol phosphate formation, but slightly enhanced the activity of phospholipase C agonists (thrombin, A1F4- complex). Activation of the CSF-1 receptor by its ligand was evidenced by the rapid activation of the Na+/H+ exchanger resulting in amiloride-sensitive cytoplasmic alkalinization (0.1-0.2 pH units) within minutes after stimulation. Whereas pertussis toxin does not affect the action of EGF, FGF, or IGF-I in CCL39 cells, it partially inhibited both DNA synthesis reinitiation and activation of Na+/H+ exchange by CSF-1, indicating that the CSF-1 receptor can communicate with a signal-transducing GTP binding protein. A point-mutated form of the c-fms gene product, in which Tyr 969, a residue negatively modulating signal transduction, had been replaced with Phe [fms (F969)], did not generate responses significantly different from those obtained with the wild-type c-fms gene product. In the absence of CSF-1, cells expressing either wild-type or fms (F969) showed a considerably higher basal level of thymidine incorporation and decreased anchorage dependence compared with parental CCL39 cells. Monoclonal antibodies that interfere with signal transduction by the human CSF-1 receptor inhibited both basal [3H]thymidine incorporation and soft agar colony formation, indicating that relaxation of growth control was dependent on CSF-1 receptor expression.
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PMID:Functional expression of the human receptor for colony-stimulating factor 1 (CSF-1) in hamster fibroblasts: CSF-1 stimulates Na+/H+ exchange and DNA-synthesis in the absence of phosphoinositide breakdown. 215 62

We have previously determined that human neutrophils and monocytes, as well as neutrophil/monocyte progenitor cells, express a subtype of P2-purinergic receptors (for ATP) which activate the inositol phospholipid signalling system. In the present study, membranes prepared from HL-60 promyelocytic leukemia cells were used to examine the mechanism by which these ATP receptors activate phosphatidylinositol-specific phospholipase C (PI-PLC) under defined in vitro conditions. Micromolar concentrations of the receptor agonists ATP, UTP, and ATP gamma S stimulated the GTP-dependent formation of inositol bisphosphate (IP2) and inositol trisphosphate (IP3) in washed membranes prepared from undifferentiated HL-60 cells prelabeled with [3H]inositol. The stimulatory effects of these nucleotides on PI-PLC appeared to be mediated through a GTP binding protein since minimal inositol polyphosphate accumulation was observed in the absence of guanine nucleotides. The increased inositol polyphosphate formation triggered by these nucleotide receptor agonists did not result from inhibition of GTP breakdown. Neither was it a consequence of increased [3H]polyphosphatidylinositol levels resulting from enhanced activity of membrane-associated PI- or PIP-kinases. Instead, the stimulated phospholipase activity was apparently receptor-mediated. The rank order of potency observed in these in vitro membrane assays (ATP = UTP greater than ATP gamma S much greater than TTP greater than CTP much greater than beta, gamma-CH-ATP) was similar to that observed with intact HL-60 cells. This order of potency appears to distinguish the P2-purinergic receptors expressed by human phagocytic leukocytes from the P2 gamma-purinergic receptors which activate PI-PLC in turkey erythrocyte membranes.
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PMID:P2-purinergic receptors activate a guanine nucleotide-dependent phospholipase C in membranes from HL-60 cells. 216 87


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