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)

Platelet-activating factor (PAF) is an unusually potent phospholipid known to be produced by neuronal cells and to modulate cerebral blood flow and metabolism. In previous studies with NCB-20 cells, we reported that PAF induced a significant mobilization of intracellular free Ca2+ ([Ca2+]i), which was inhibited by PAF antagonists. The increase was the result of release from intracellular stores and influx from extracellular sources. The present study was designed to characterize further PAF receptor-mediated cellular signal-transduction mechanisms in myo-[3H]inositol-labeled cells. PAF induced a concentration-dependent increase in phosphatidylinositol (Pl) metabolism, with EC50 values of 1.96 +/- 0.62 nM and 1.12 +/- 0.50 nM for inositol trisphosphate (IP3) and inositol monophosphate (IP1) formation, respectively (four experiments). The maximal production of IP3 and IP1 induced by 50 nM PAF was 254 +/- 34% and 178 +/- 25% over the basal, respectively (four experiments). PAF-induced Pl metabolism was concentration-dependently inhibited by the PAF antagonist BN50739, with an IC50 value of 6.48 +/- 0.52 nM (four experiments). The protein kinase C (PKC) activator phorbol 12,13-dibutyrate concentration-dependently inhibited PAF-induced Pl metabolism and [Ca2+]i mobilization in NCB-20 cells, of NCB-20 cells with pertussis toxin (PTX) resulted in a concentration-dependent inhibition of PAF-induced IP3 production and intracellular Ca2+ release, with a maximal reduction of 66.9 +/- 3.5% and 63 +/- 6.1%, respectively, at 300 ng/ml PTX. PTX in the presence of [32P]NAD specifically [32P]ADP-ribosylated a 38-kDa protein in membranes prepared from NCB-20 cells. Pretreatment of the cells with PTX resulted in a concentration-dependent inhibition of subsequent 32P-labeling of the toxin substrate in the membranes and correlated with the uncoupling of PAF-induced IP3 formation. PAF (0.01-10 nM) elicited a concentration-related stimulation in guanosine 5'-O-(3-[35S]) triphosphate ([35S]GTP gamma S) binding to G alpha i(1,2) proteins, which was inhibited by the PAF antagonist BN50739. PAF at 10 nM also increased [35S]GTP gamma S binding to G alpha s and G alpha o. PAF-evoked activation of G alpha i(1,2) and G alpha o was reduced by preincubation with PTX. Our results reveal that neuronal cells possess PAF receptors linked through guanine nucleotide-binding proteins to phospholipase C and receptor-operated Ca2+ channels that are regulated by PKC. Both PTX-sensitive and -insensitive guanine nucleotide-binding proteins appear to couple the PAF receptor to activation of phospholipase C and the increase in [Ca2+]i. These results contribute to the further understanding of the mechanisms behind PAF actions on neuronal cells.
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PMID:Platelet-activating factor stimulates phosphoinositide turnover in neurohybrid NCB-20 cells: involvement of pertussis toxin-sensitive guanine nucleotide-binding proteins and inhibition by protein kinase C. 131 8

To assess sites and mechanism of action of prostaglandin E2 (PGE2) on water permeability (PF), we determined PGE2 effects on antidiuretic hormone (ADH)- and adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated PF in rat terminal inner medullary collecting ducts perfused in vitro. PGE2 (10(-7) M) reversibly inhibited ADH-stimulated PF (1.131 +/- 192 to 532 +/- 208 microns/s). In contrast to that observed in rabbit, PGE2 also inhibited an established PF response to the exogenous cAMP analogue 8-p-(chlorophenylthio)-cAMP (696 +/- 107 to 399 +/- 99 microns/s). PGE2 alone had no effect on PF. The protein kinase C inhibitor staurosporine (10(-8) M) blocked PGE2-mediated inhibition of cAMP-stimulated PF. PGE2 caused a rapid spikelike increase in intracellular calcium [( Ca2+]i) followed by a stable elevation above basal values. Only the latter effect was abolished in a zero calcium bath. Neither staurosporine nor cAMP altered the [Ca2+]i response. These studies are the first to demonstrate PGE2-mediated inhibition of an established PF response to cAMP independent of changes in intracellular cAMP. The pattern of [Ca2+]i release and sensitivity to staurosporine suggests that this effect is mediated via signaling through phospholipase C. The results underscore the importance of species differences, axial heterogeneity, and/or in vivo conditioning for functional expression of cellular signaling pathways.
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PMID:PGE2 inhibits water permeability at a post-cAMP site in rat terminal inner medullary collecting duct. 131 24

Influenza A virus (IAV) causes both activation and deactivation of the human neutrophil, which may, respectively, contribute to host defense against the virus and enhanced susceptibility to bacterial superinfection. We have shown that certain features of neutrophil activation by IAV are distinctive compared with activation by chemoattractants in terms of both the stoichiometry of the respiratory burst response and the signal transduction events that precede it. We here demonstrate that related myxoviruses as well as sialic acid-binding lectins elicit a respiratory burst response similar to that induced by IAV, in which hydrogen peroxide is formed with minimal accompanying superoxide generation. Brief preincubation of neutrophils with these agents fully inhibits subsequent activation by IAV, implying that they are binding to the same surface membrane components as IAV. Preincubation with Limax flavus agglutinin (LFA) does, in fact, substantially reduce binding of radiolabeled IAV to the neutrophil. This lectin, like IAV, both activates and deactivates the neutrophil. As in the case of IAV, LFA-induced activation (1) is mediated via stimulation of phospholipase C, (2) is pertussis toxin insensitive, and (3) entails a lesser contribution of calcium influx than is the case for chemoattractants.
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PMID:Anomalous features of human neutrophil activation by influenza A virus are shared by related viruses and sialic acid-binding lectins. 131 44

Previous work from this laboratory has shown that the electrically evoked release of enkephalin from the guinea pig myenteric plexus is regulated by an opiate receptor-mediated, concentration-dependent mechanism. Low concentrations (nanomolar) of opioids enhance release, whereas higher concentrations (10-100 nM) inhibit release. Each opioid effect is mediated by a different guanine nucleotide-binding protein. We now demonstrate that activation of cholinergic receptors in the myenteric plexus is a prerequisite for opioid excitatory effects, but not inhibitory effects, on enkephalin release. Pretreatment with the muscarinic cholinergic receptor antagonist atropine abolishes the opioid facilitation of stimulated enkephalin release but does not alter the inhibition of release that is observed with higher concentrations of opioid agonist. Exposure to the calcium ionophore A23187 overcomes the abolishment of opioid enhancement of enkephalin release produced by cholinergic receptor blockade. In tissue treated with both atropine and A23187, the magnitude of the opioid enhancement of release is indistinguishable from that observed in untreated preparations. This suggests that the lack of stimulation-induced generation of elevated cytosolic calcium is responsible for the abolishment of facilitory opioid effects when cholinergic receptors are blocked. The known coupling of muscarinic receptors to phospholipase C activation and the generation of inositol trisphosphate (which elevates cytosolic calcium) could suggest that this second messenger is critical for the manifestation of opioid facilitation of enkephalin release.
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PMID:Opioid enhancement of evoked [Met5]enkephalin release requires activation of cholinergic receptors: possible involvement of intracellular calcium. 131 58

Extracellular ATP and UTP caused increases in the concentration of cytoplasmic free calcium ([Ca2+]i) and the intracellular level of inositol 1,4,5-trisphosphate (IP3), a second messenger for calcium mobilization, prior to the release of prostacyclin (PGI2) from cultured bovine pulmonary artery endothelial (BPAE) cells. The agonist specificity and dose-dependence were similar for nucleotide-mediated increases in IP3 levels, [Ca2+]i and PGI2 release. An increase in [Ca2+]; and PGI2 release was observed after addition of ionomycin, a calcium ionophore, to BPAE cells incubated in a calcium-free medium. The addition of ATP to the ionomycin-treated cells caused no further increase in [Ca2+]i or PGI2 release. The inability of ATP to cause an increase in [Ca2+]i or PGI2 release in ionomycin-treated cells was apparently due to the ionomycin-dependent depletion of intracellular calcium stores since the subsequent addition of extracellular calcium caused a significant increase in both [Ca2+]i and PGI2 release. Introduction of BAPTA, a calcium buffer, into BPAE cells inhibited ATP-mediated increases in [Ca2+]i and PGI2 release, further evidence that PGI2 release is dependent upon an increase in [Ca2+]i. The increase in [Ca2+]i elicited by ATP apparently caused the activation of a calmodulin-dependent phospholipase A2 since trifluoperazine, an inhibitor of calmodulin, and quinacrine, an inhibitor of phospholipase A2, prevented the stimulation of PGI2 release by ATP. Furthermore, ATP caused the specific hydrolysis of [14C]arachidonyl-labeled phosphatidylcholine and the generation of free arachidonic acid, the rate-limiting substrate for PGI2 synthesis, prior to the release of PGI2 from BPAE cells. These findings suggest that the increase in PGI2 release elicited by ATP and UTP is at least partially dependent upon a phospholipase C-mediated increase in [Ca2+]i and the subsequent activation of a phosphatidylcholine-specific phospholipase A2. ATP analogs modified in the adenine base or phosphate moiety caused PGI2 release with a rank order of agonist potency of adenosine 5'-O-(2-thiodiphosphate) (ADP beta S) greater than 2-methylthioATP (2-MeSATP) greater than ATP, whereas alpha, beta methyleneATP and beta, gamma methyleneATP had no effect on PGI2 release.
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PMID:Mechanisms by which extracellular ATP and UTP stimulate the release of prostacyclin from bovine pulmonary artery endothelial cells. 131 59

The dinoflagellate toxin maitotoxin (MTX) elicited a sustained increase of [Ca2+]i in C6 glioma cells. This response was inhibited by SK&F 96365, a blocker of receptor-mediated calcium entry. In C6 cells, endothelin-1 elicited a rapid but transient increase in [Ca2+]i, followed by a smaller sustained increase. SK&F 96365 inhibited the sustained increase in [Ca2+]i. In both C6 glioma cells and RIN insulinoma cells, MTX elicited a marked influx of 45Ca2+. SK&F 96365 inhibited MTX-induced 45Ca2+ influx by 95% at 30 microM. The L-type calcium channel blocker nifedipine, even at 10 microM, inhibited MTX-induced calcium uptake by only 20% in RIN cells and by only 10% in C6 cells. MTX elicited calcium-dependent phosphoinositide breakdown in both C6 and RIN cells. In both cell lines, the MTX-induced phosphoinositide breakdown was inhibited by 90% by SK&F 96365 at 30 microM. Endothelin-1 and carbamylcholine elicited phosphoinositide breakdown in C6 cells and RIN cells, respectively. The stimulations were unaffected by the presence of SK&F 96365 up to 100 microM. In RIN insulinoma cells, MTX elicited calcium-dependent release of insulin. SK&F 96365 at 30 microM inhibited MTX-induced insulin release by 75%, whereas nifedipine, even at 30 microM, inhibited release by only 10%. The blockade of MTX-induced responses by SK&F 96365 indicates that MTX increases intracellular calcium by interacting directly with a calcium-entry system that is similar, in its sensitivity to SK&F 96365, to the calcium-entry system activated by receptors that elicit phosphoinositide breakdown. Activation of phospholipase C and hormone release by MTX also are blocked by SK&F 96365 and, thus, may be secondary to the activation of such a calcium-entry system.
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PMID:Maitotoxin effects are blocked by SK&F 96365, an inhibitor of receptor-mediated calcium entry. 131 15

DDT1-MF2 smooth muscle cells demonstrated a robust phospholipase C response to norepinephrine, as detected by inositol phosphate accumulation. A selective A1-adenosine receptor agonist, cyclopentyladenosine, caused only a minor stimulation of phospholipase C, which was eliminated in the absence of added extracellular calcium. The simultaneous addition of norepinephrine and cyclopentyladenosine resulted in a synergistic increase in phosphoinositide hydrolysis either in the absence or in the presence of external calcium. In the presence of external calcium and a calcium ionophore, and adenosine agonist caused a significant stimulation of phosphoinositide hydrolysis without the addition of norepinephrine. Influx of extracellular calcium through voltage-sensitive calcium channels did not appear to be required to observe an effect of cyclopentyladenosine, because neither calcium channel antagonists (nifedipine, verapamil, and LaCl3) nor a chelator of extracellular calcium (ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid) were able to alter the degree of potentiation of norepinephrine-stimulated phosphoinositide hydrolysis due to the adenosine agonist. On the other hand, buffering of intracellular calcium concentration with the membrane-permeant calcium chelator quin2 blocked the potentiation. This blockade of potentiation by quin2 was reversed by the addition of extracellular calcium. Agents that stimulated cAMP production or membrane-permeable analogues of cAMP also blocked the action of the adenosine agonist to potentiate norepinephrine-stimulated phosphoinositide hydrolysis. This effect of cAMP was less pronounced in the presence of elevated extracellular calcium and was abolished in the presence of a calcium ionophore. When norepinephrine-stimulated calcium transients were quantitated using fura-2 fluorescence, a reduction in the amplitude of the calcium response was observed in the presence of forskolin. Conversely, both the amplitude and the duration of the calcium response were enhanced by the addition of the adenosine agonist. The results of these studies suggest that the mechanism by which adenosine receptors enhance the stimulation of phosphoinositide hydrolysis is dependent upon a rise in intracellular Ca2+ concentration resulting from the simultaneous activation of alpha 1-adrenergic receptors. The results further suggest that cAMP inhibits this mechanism by decreasing the norepinephrine-stimulated rise in intracellular Ca2+ concentration.
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PMID:Competitive regulation of phospholipase C responses by cAMP and calcium. 131 17

Atherogenesis is associated with alterations in the properties of different cell types, including monocytes/macrophages (foam cell formation), platelets (increased aggregation), endothelial cells (injury), and smooth muscle cells (SMCs) (lipid accumulation or foam cell formation). Oxidized low density lipoproteins (ox-LDL) play a key role in this vascular pathology. This study investigated the ability of ox-LDL to elicit chemical signaling events in cultured human vascular smooth muscle cells (VSMCs). Ox-LDL was found to stimulate phospholipase C-mediated phosphoinositide turnover in human VSMCs. This response occurred rapidly (within 1 minute) and at low concentrations of ox-LDL (half-maximal effective concentration, approximately 5 micrograms/ml). Ox-LDL-stimulated inositol phosphate accumulation in human VSMCs was inhibited by pretreatment of cells with phorbol 12-myristate 13-acetate and with compounds that elevate cyclic AMP or cyclic GMP. Ca2+ antagonists also blocked the effects of ox-LDL on phosphoinositide turnover. Inhibitors of receptor-endocytotic processes (including receptor clustering, cross-linking, and cytoskeleton-dependent internalization) effectively prevented ox-LDL-induced inositol phosphate generation. The data suggest that ox-LDL promotes phospholipase C-mediated phosphoinositide turnover in a manner analogous to that for other Ca(2+)-mobilizing hormones. The results also support an association between phosphoinositide turnover and receptor-mediated endocytosis. Prevention of the direct effects of ox-LDL on SMCs could prove an interesting therapeutic avenue for the prevention of atherosclerosis.
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PMID:Oxidized low density lipoproteins stimulate phosphoinositide turnover in cultured vascular smooth muscle cells. 131 38

The accumulation of both Inositol-(1,4,5)-trisphosphate (IP3) and Inositol-(1,3,4,5)-tetrakisphosphate (IP4) after hormonal stimulation has a physiological role, possibly in altering Ca2+ levels in cardiac tissue. However, the accumulation of inositol polyphosphate under pathophysiological conditions has not been studied. In our experiments the metabolism of phatidylinositol and IP3 in cardiac myocytes as investigated. It was shown that basal levels of cytosolic phosphatidylinositol specific phospholipase C (PI-PLC), phosphatidylinositol-(4,5)-bisphosphate specific phospholipase C (PIP2-PLC) activities markedly increased in stroke-prone spontaneously hypertensive rats (SHRSP) with age compared with age matched Wistar Kyoto rats (WKY). IP3 kinase and IP3 phosphatase activities also increased in SHRSP hearts with age. Their activities increased in WKY, but to a lesser extent than in SHRSPs. These data suggest that a PI turnover pathway such as the phosphatidylinositol 4,5-bisphosphate-IP3-Ca2+ pathway or the diacylglyceride-protein kinase C pathway may have an important role in the development of hypertrophy in SHRSP heart.
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PMID:Phosphatidylinositol and inositolphosphatide metabolism in hypertrophied rat heart. 131 48

Spontaneously hypertensive rats (SHR), which develop hypertension approximately 10 weeks after birth, are considered to provide a good animal model for human essential hypertension. We report here that the abnormal activation of phospholipase C delta 1 (PLC-delta 1) may be one of the main causes of hypertension. Levels of the second messengers inositol 1,4,5-trisphosphate and diacylglycerol are found to be higher in the aortas of 12-week-old SHR than in age-matched normotensive Wistar-Kyoto rats (WKY), although the levels in the aortas of 7-week-old SHR, which have normal blood pressure, are the same as in WKY. Moreover, PLC activity is also higher in the aortas of 12-week-old SHR. Judging from Western blot analysis and immunoabsorption of PLCs, this activation is found to be due to that of PLC-delta 1. PLC-delta 1 from rat aorta is expressed significantly from 7 to 12 weeks, which correlates with the development of hypertension in SHR. The activity of PLC-delta 1 in the aortas of 12-week-old SHR is more markedly activated at low Ca2+ concentration than that of age-matched WKY. These results suggest that the abnormal enhancement of PLC-delta 1 activity is responsible for accumulation of inositol 1,4,5-trisphosphate and diacylglycerol, leading to continuous hypertonicity of vascular smooth muscle in SHR. The activity of PLC-delta 1 in the aortas of 12-week-old SHR is significantly higher at low Ca2+ concentration than that of normotensive WKY.
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PMID:Enhancement of phospholipase C delta 1 activity in the aortas of spontaneously hypertensive rats. 131 6


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