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)

Acetylcholine (ACh)-activated channel properties were examined on an aneural culture of chick embryo myotubes by using patch-clamp techniques. Changes in conductance, open time and closed time were induced by the selective activator of the calcium- and phospholipid-dependent C-kinase (PKc), 12-O-tetradecanoylphorbol-13-acetate (TPA). The action of TPA was mimicked by exogenous phospholipase C and was blocked by the PKc inhibitor, 1-(5-isoquinolinylsulphonyl)-2-methyl-piperazine. In addition to its gating action, ACh was shown to stimulate phosphoinositide turnover and to translocate PKc from the cytosol to the cell membrane. Both these ACh-induced effects were inhibited by curare and not substantially affected by atropine. Bath-applied ACh outside the patch-pipette in the cell-attached patch-clamp mode, had a strong effect on the ACh-activated channels in the patch membrane, in a way that resembled the action of TPA. These findings raise the possibility that ACh regulates its own nicotinic receptors through the C-kinase system.
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PMID:Acetylcholine may regulate its own nicotinic receptor-channel through the C-kinase system. 288 74

The presence of a phospholipase A2 (PLA2) activity in rabbit neutrophil membrane preparation that is able to release [1-14C]oleic acid from labelled Escherichia coli has been demonstrated. The activity is critically dependent on the free calcium concentration and marginally stimulated by GTP gamma S. More than 80% of maximal activity is reached at 10 microM-Ca2+. The chemotactic factor, fMet-Leu-Phe, does not stimulate the PLA2 activity in this membrane preparation. Pretreatment of the membrane preparation, under various experimental conditions, or intact cells, before isolation of the membrane with phorbol 12-myristate 13-acetate (PMA), does not affect PLA2 activity. Addition of the catalytic unit of cyclic AMP-dependent kinase to membrane preparation has no effect on PLA2 activity. Pretreatment of the intact neutrophil with dibutyryl-cAMP before isolation of the membrane produces a small but consistent increase in PLA2 activity. The activity of PLA2 in membrane isolated from cells treated with the protein kinase inhibitor 1-(5-isoquinolinesulphonyl)-2-methyl piperazine dihydrochloride (H-7) is significantly decreased. Furthermore, although the addition of PMA to intact rabbit neutrophils has no effect on the release of [3H]arachidonic acid from prelabelled cells, it potentiates significantly the release produced by the calcium ionophore A23187. This potentiation is not due to an inhibition of the acyltransferase activity. H-7 inhibits the basal release of arachidonic acid but does not inhibit the potentiation by PMA. These results suggest several points. (1) fMet-Leu-Phe does not stimulate PLA2 directly, and its ability to release arachidonic acid in intact neutrophils is mediated through its action on phospholipase C. (2) The potentiating effect of PMA on A23187-induced arachidonic acid release is most likely due to PMA affecting either the environment of PLA2 and/or altering the organization of membrane phospholipids in such a way as to increase their susceptibility to hydrolysis. (3) The intracellular level of cyclic AMP probably does not directly affect the activity of PLA2.
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PMID:Demonstration of calcium-dependent phospholipase A2 activity in membrane preparation of rabbit neutrophils. Absence of activation by fMet-Leu-Phe, phorbol 12-myristate 13-acetate and A-kinase. 312 81

The tumor promoter phorbol ester (PMA) has been shown to stimulate protein kinase C (PKC) in MDCK cells. At the concentrations that produce stimulation of PKC, PMA (100 microM) inhibits BK-induced I1,4,5P3 (IP3) formation and calcium transients in these cells. 1-5-isoquinolinyl-2-methyl-piperazine (H7) a known inhibitor of PKC in MDCK cells reverses the effect of PMA on BK-stimulated IP3 formation and Ca2+ transients in these cells. PMA also stimulates arachidonate release which can be inhibited by preincubation with H7. A dual mechanism of regulation by PKC at the level of phospholipase C (down regulation) and phospholipase A2 (stimulation) is suggested in these cells.
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PMID:Protein kinase C modulates phospholipase C and increases arachidonic acid release in bradykinin stimulated MDCK cells. 313 68

High blood pressure is one of the major risk factors for atherosclerosis. In this study, we examined the effects of pressure on cell proliferation and DNA synthesis in cultured rat vascular smooth muscle cells. Pressure without shear stress and stretch promotes cell proliferation and DNA synthesis in a pressure-dependent manner. Pressure-induced DNA synthesis was inhibited significantly by the phospholipase C (PLC) inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, the protein kinase C inhibitor H-7, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine, staurosporine, and the tyrosine kinase inhibitor ([3,4,5-trihydroxyphenyl]methylene)propanedinitrile. To clarify whether activation of PLC and calcium mobilization are involved in pressure-induced DNA synthesis, production of 1,4,5-inositol trisphosphate (IP3) and intracellular Ca2+ was measured. Pure pressure increased IP3 and intracellular Ca2+ in a pressure-dependent manner. The increases in both IP3 and intracellular Ca2+ were inhibited significantly by 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate. This study demonstrates a novel cellular mechanism whereby pressure regulates DNA synthesis in vascular smooth muscle cells, possibly via activation of PLC and protein kinase C.
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PMID:Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells. 818 28

1,25-Dihydroxyvitamin D-3 (1,25(OH)2D3) which activates the phospholipase C (PLC)-protein kinase C (PKC) signalling pathway, induces within 1 min a dose-dependent (10(-11)-10(-7) M) increase in the release of [3H]arachidonic acid ([3H]AA) from prelabeled embryonic chick myoblasts. The response is dependent on extracellular calcium, since it is suppressed by EGTA and nifedipine, a Ca(2+)-channel blocker, and is mimicked by the calcium ionophore A23187. 1,25(OH)2D3-induced release of [3H]AA is not affected by neomycin (0.5 mM), an inhibitor of phosphoinositide hydrolysis. 12-o-tetradecanoylphorbol-13-acetate (TPA), a PKC activator, induces an extracellular Ca(2+)-independent release of [3H]AA and amplifies the release of AA stimulated by 1,25(OH)2D3. 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H7), a PKC inhibitor, markedly suppressed TPA as well as 1,25(OH)2D3-induced [3H]AA release. Down-regulation of cellular PKC abolishes the effect of the phorbol ester, and partially inhibits 1,25(OH)2D3-induced [3H]AA release. Temporally correlated with AA liberation, the hormone increases the formation of lysophosphatidylcholine (lysoPC) and lysophosphatidylethanolamine (lysoPE) and decreases the cellular content of PC and PE. These results indicate that part of AA release by 1,25(OH)2D3 derives from PLA2 activation and that the effects of the hormone are mediated by PKC in a mode independent of phosphoinositide hydrolysis by PLC.
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PMID:1,25-Dihydroxyvitamin D-3 induces arachidonate mobilization in embryonic chick myoblasts. 839 56

We studied H2O2-induced contractions of isolated rabbit intrapulmonary arteries mounted in standard tissue baths. All vessels were pretreated with a thromboxane A2/prostaglandin H2 receptor antagonist, SQ 29,548, to block immediate transient contractions to H2O2 and to isolate slowly developing sustained contractions. When exposed to H2O2 (0.1, 0.2, 0.3, 0.6, and 1.0 mM) for 30 min, vessels contracted in (0.1, 0.2, 0.3, 0.6, and 1.0 mM) for 30 min, vessels contracted in a concentration-dependent fashion between 0.1 and 0.3 mM H2O2; contractions at 0.6 and 1.0 mM H2O2 were not significantly different from those at 0.3 mM H2O2. During recovery (90 min) from H2O2 exposures, baseline tension was significantly greater, but active tension (10 microM phenylephrine) was significantly less for vessels previously exposed to 0.6 and 1.0 mM H2O2. Contractions to 0.3 mM H2O2 were not blunted by the following interventions: 1) endothelium rubbing, 2) incubation in Ca(2+)-free 100 microM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) Krebs-Ringer solution, 3) incubation in the Ca(2+)-free solution and depletion of ryanodine (20 microM)-sensitive Ca(2+) stores, or 4) pretreatment with the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-3-methyl-piperazine (20 microM). However, contractions were depressed by approximately 50% when vessels were pretreated with the phospholipase C/serine esterase inhibitor 2-nitro-4-carboxy-phenyl-N,N-diphenylcarbamate (50 microM). These results suggest that slow-developing contractions to H2O2 are concentration dependent and may result, in part, from activation of a serine esterase(s) and/or phospholipase C.
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PMID:Characterization and mechanisms of H2O2-induced contractions of pulmonary arteries. 849 68

The mitogenic effect of recombinant human erythropoietin (rHuEpo) on primary cultures of neonatal rat cardiac myocytes was observed. rHuEpo triggered a dose-dependent increase in myocyte proliferation. The hormone effect over optimally grown control culture 1 day after addition was maximum with 0.5 U/ml and was inhibited with anti-rHuEpo. Inhibitors of enzymatic pathways known to be involved in the cytokines intracellular mechanism such as genistein (tyrosine kinase inhibitor), 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (phospholipase C [PLC] inhibitor), and 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (protein kinase C [PKC] inhibitor) prevented the mitogenic action of rHuEpo. Also the inhibition of Na(+)-K(+)-ATPase activity by ouabain blunted the stimulatory action of rHuEpo on cell proliferation. The mitogenic action of the hormone was correlated with cardiac membrane paranitrophenylphosphatase (pNPPase) and PKC activity, since concentrations of rHuEpo that stimulate DNA synthesis increased pNPPase and PKC activity. Moreover, the enzymatic inhibition of tyrosine kinase, PLC, and PKC attenuated the stimulatory action of rHuEpo upon cardiac pNPPase activity. In this paper we demonstrate a non-hematopoietic action of rHuEpo showing both mitogenic and enzymatic effect upon primary myocyte cell culture and on pNPPase activity of neonatal rat heart. These effects are related to the capacity of rHuEpo to stimulate Na(+)-K(+)-ATPase activity and appear to be secondary to the activation of tyrosine kinase and PKC, indicating that in the rHuEpo mediated mitogenic action on cardiomyocytes involves the activation of the same enzymatic pathways that have been described by other cytokines in different tissues.
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PMID:Mitogenic effect of erythropoietin on neonatal rat cardiomyocytes: signal transduction pathways. 865

There are many examples of a single receptor coupling directly to more than one cellular signal transduction pathway. Although traditional receptor theory allows for activation of multiple cellular effectors by agonists, it predicts that the relative degree of activation of each effector pathway by an agonist (relative efficacy) must be the same. In the current experiments, we demonstrate that agonists at the human serotonin2A (5-HT2A) and 5-HT2C receptors activate differentially two signal transduction pathways independently coupled to the receptors [phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A2 (PLA2)-mediated arachidonic acid (AA) release]. The relative efficacies of agonists differed depending on which signal transduction pathway was measured. Moreover, relative to 5-HT, some 5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activated the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favored the PLA2-AA pathway. In contrast, when two dependent responses were measured (IP accumulation and calcium mobilization), agonist relative efficacies were not different. These data strongly support the hypothesis termed "agonist-directed trafficking of receptor stimulus" recently proposed by Kenakin [Trends Pharmacol Sci 16:232-238 (1995)]. Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy. Rational drug design that optimizes preferential effector activity within a group of receptor-selective drugs holds the promise of increased selectivity in clinically useful agents.
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PMID:Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. 965 94

Using the fluorescent Ca2+ indicator fura-2, we demonstrated that, in a single NG108-15 cell, acute repetitive challenge with leucine-enkephalin (EK) results in a gradual reduction of the increase of the cytosolic Ca2+ concentration ([Ca2+]i) at agonist exposure times of 90 s or less; increasing the EK exposure time of each challenge from 30 to 90 s results in greater desensitization, with complete desensitization occurring at 90 s exposure. Similar results are seen with ATP. In opioid-desensitized cells, bradykinin can still induce a marked [Ca2+]i increase, while exposure of desensitized cell to 50 mM K+ restores the response EK-induced, suggesting a role of intracellular Ca2+ stores in the desensitization process. Pretreatment of cells with certain protein kinase inhibitors, including N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA1004) and staurosporine, prevented desensitization, while others, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) and {1-[N, O-bis-(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenyl-piperazine (KN-62), had no effect. In contrast, activation of protein kinase C by phorbol 12-myristate 13-acetate promoted desensitization. Thus, the desensitization is dependent on protein phosphorylation. HA1004 alone did not alter EK- or bradykinin-induced inositol 1,4, 5-trisphosphate (IP3) generation; however, the inhibitory effect of calyculin A on EK- or bradykinin-induced IP3 generation was reversed by HA1004. In addition, in the presence of HA1004, the blockade of Ca2+ influx by either verapamil or removal of extracellular Ca2+ or the depletion of Ca2+ pools by thapsigargin still led to desensitization, suggesting that phosphorylation does not alter the activity of the Ca2+ transporters involved in Ca2+ influx and Ca2+ release. Our results imply that emptying of intracellular Ca2+ stores and protein phosphorylation in the phospholipase C signaling pathway play roles in the process of desensitization.
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PMID:Phosphorylation promotes the desensitization of the opioid-induced Ca2+ increase in NG108-15 cells. 1008 17

The purpose of this study was to characterize pharmacologically the 5-HT receptor(s) mediating contraction in the mouse aorta and the pathways these receptors are coupled with to mediate contraction. We hypothesized that a 5-HT2A receptor, as in the rat, mediates contraction by activating L-type calcium channels, phospholipase C (PLC), and tyrosine kinase(s). Endothelium-denuded aortic strips were placed in a tissue bath for measurement of isometric contractile force. 5-HT, the 5-HT2A receptor agonist alpha-methyl-5-HT, and partial 5-HT2A receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (+/--DOI) caused the most potent and efficacious contraction. The 5-HT(1E/1F) receptor agonist BRL 54443 also induced contraction (-log EC(50) = 6.52); however, the 5-HT2A receptor antagonist ketanserin antagonized this contraction. Our hypothesis was further supported by the finding that antagonists with affinity for the 5-HT2A receptor, ketanserin, 1-(1-naphthyl)piperazine, spiperone, and LY53857, reduced 5-HT-induced contraction. A correlation of 0.927 was found between literature-derived compound binding affinities for the agonists and antagonists at the 5-HT2A receptor of the rat and the data generated in our experiments (-log EC(50) and pK(B) values). The L-type calcium channel blockers nifedipine and nitrendipine, PLC inhibitor 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate, and tyrosine kinase inhibitors genistein and PD 098,059 all shifted and/or reduced maximum contraction to 5-HT. We conclude that contraction to 5-HT in the mouse aorta is mediated primarily by a 5-HT2A receptor and is coupled to L-type calcium channels, PLC, and tyrosine kinases.
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PMID:Characterization of the serotonin receptor mediating contraction in the mouse thoracic aorta and signal pathway coupling. 1125 31


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