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)

We have previously reported that LiCl increases considerably the cytotoxic activity of TNF towards some transformed cell lines such as L929. Here we show that treatment of these cell lines with the combination of TNF and LiCl leads to the prolonged accumulation of inositol monophosphate, inositol bisphosphate, and inositol trisphosphate, whereas treatment with TNF or LiCl alone did not. In contrast, both a LiCl-unresponsive TNF-sensitive cell line and TNF-resistant cell lines did not respond with increased accumulation of inositol phosphates (IPn) upon treatment with the combination of TNF and LiCl. Furthermore, the combination of TNF and LiCl induced a transient increase in cytidine diphosphate-diacylglycerol in L929 cells. Increased IPn and cytidine diphosphate-diacylglycerol accumulation preceded the onset of cell killing by approximately 1 h. TNF-mediated cytotoxicity and TNF-induced IPn accumulation were equally sensitive to inhibition by the phospholipase inhibitor neomycin and to stimulation by the protein kinase inhibitor staurosporine. Characterization of the inositol bisphosphate isomers by HPLC analysis revealed that the TNF + LiCl-induced increase in IPn levels was due to activation of a phospholipase C and not of a phospholipase D. In contrast to TNF, several other cytotoxic agents did not increase IPn production upon application in the presence of LiCl. The TNF + LiCl-induced increase in inositol triphosphate suggests a role for intracellular Ca2+ mobilization in TNF action. Moreover, several agents that lower the intracellular Ca2+ concentration inhibited TNF cytotoxicity. In conclusion, our data provide evidence that TNF cytotoxicity and its enhancement by LiCl are mediated by increased IPn accumulation resulting in Ca2+ mobilization.
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PMID:Enhancement of tumor necrosis factor cytotoxicity by lithium chloride is associated with increased inositol phosphate accumulation. 839 97

The response to a number of agents has been compared in two short-term assays used for the detection of virus inducers and tumor promoters: (i) induction of the EBV-DR-promoter in Raji cells, as measured by DR-CAT induction (DR-CAT test) and (ii) induction of the oxidative burst in human PMN, as measured by chemiluminescence in the presence of luminol or lucigenin (CL test). In order to validate the two assays, we have investigated the responses to 12-O-tetradecanoyl-phorbol-13-acetate (TPA), 1,2-dioctanoylglycerol (DAG), phospholipase C (PLC EC-3-1-4-30) and ionophore A23187, which are active in both systems: arachidonic acid, linoleic acid and NaCl were found active only in the CL test. Staurosporine (protein kinase inhibitor), tamoxifen (estrogen antagonist and protein kinase C inhibitor), forskolin (protein kinase A activator), R59949 (diacylglycerol kinase inhibitor), curcumin and N-acetyl-L-cysteine (scavengers of reactive oxygen species) and NaCl acted as inhibitors. A good concordance of the EC50 values of inducing substances was found between the two assays, except for A23187 and DAG, which were required at much higher concentrations in the DR-CAT test. The inhibition patterns by the panel of inhibitors revealed similarities and discrepancies in the induction pathways between the two systems, providing information on their mode of action. The two assays, which complement each other, were shown to detect a number of known or suspected EBV inducers or tumor promoters, and thus appear useful for screening of new compounds or mixtures as well as of potential antiviral and antipromoting substances.
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PMID:Validation of two test systems for detecting tumor promoters and EBV inducers: comparative responses of several agents in DR-CAT Raji cells and in human granulocytes. 839 78

Metabotropic glutamate receptors (mGluRs) control intracellular signaling cascades through activation of G proteins. The inwardly rectifying K+ channel, GIRK, is activated by the beta gamma subunits of G proteins and is widely expressed in the brain. We investigated whether an interaction between mGluRs and GIRK is possible, using Xenopus oocytes expressing mGluRs and a cardiac/brain subunit of GIRK, GIRK1, with or without another brain subunit, GIRK2. mGluRs known to inhibit adenylyl cyclase (types 2, 3, 4, 6, and 7) activated the GIRK channel. The strongest response was observed with mGluR2; it was inhibited by pertussis toxin (PTX). This is consistent with the activation of GIRK by Gi/Go-coupled receptors. In contrast, mGluR1a and mGluR5 receptors known to activate phospholipase C, presumably via G proteins of the Gq class, inhibited the channel's activity. The inhibition was preceded by an initial weak activation, which was more prominent at higher levels of mGluR1a expression. The inhibition of GIRK activity by mGluR1a was suppressed by a broad-specificity protein kinase inhibitor, staurosporine, and by a specific protein kinase C (PKC) inhibitor, bis-indolylmaleimide, but not by PTX, Ca(2-)chelation, or calphostin C. Thus, mGluR1a inhibits the GIRK channel primarily via a pathway involving activation of a PTX-insensitive G protein and, eventually, of a subtype of PKC, possibly PKC-mu. In contrast, the initial activation of GIRK1 caused by mGluR1a was suppressed by PTX but not by the protein kinase inhibitors. Thus, this activation probably results from a promiscuous coupling of mGluR1a to a Gi/Go protein. The observed modulations may be involved in the mGluRs effects on neuronal excitability in the brain. Inhibition of GIRK by phospholipase C-activating mGluRs bears upon the problem of specificity of G protein (GIRK interaction) helping to explain why receptors coupled to Gq are inefficient in activating GIRK.
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PMID:Positive and negative coupling of the metabotropic glutamate receptors to a G protein-activated K+ channel, GIRK, in Xenopus oocytes. 910 6

5-Hydroxytryptamine type 2A receptors (5-HT2A) are G protein-coupled receptors that increase intracellular Ca2+ concentrations via activation of phospholipase C-beta and elevation of myo-inositol-1,4,5-triphosphate levels. In the central nervous system, these receptors are involved in regulating sleep and alertness. We now report that ethanol inhibited (IC50 = 41 mM) 5-HT2A receptor-induced Ca2+-dependent Cl- currents in Xenopus laevis oocytes. Pharmacologically relevant concentrations of other n-alcohols (propanol to octanol) also inhibited 5-HT responses; however, longer-chain alcohols (decanol, undecanol and dodecanol) had little or no effect. The protein kinase C inhibitor GF109203X and the nonspecific protein kinase inhibitor staurosporine abolished the inhibitory effects of ethanol and octanol on 5-HT2A receptors. GF109203X enhanced 5-HT2A receptor function when administered alone. In addition, the volatile anesthetics halothane and 1-chloro-1,2,2-trifluorocyclobutane decreased 5-HT2A responses in a concentration-dependent manner. The inhibitory effects of the volatile anesthetics were also attenuated in oocytes treated with GF109203X. The intravenous anesthetics propofol, ketamine, pentobarbital and etomidate did not affect 5-HT2A receptor function. The modulation of 5-HT2A receptor-dependent current was also investigated using two novel halogenated compounds that do not produce anesthesia. The nonanesthetic compound 2,3-chloro-octafluorobutane had no effects on 5-HT-induced currents; however, the nonanesthetic compound 1,2-dichlorohexafluorocyclobutane had an inhibitory effect at lower concentrations than the predicted anesthetic concentration. Thus, 5-HT2A receptors are inhibited by alcohols and volatile anesthetics, and these actions are dependent on protein kinase C.
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PMID:Inhibition of 5-hydroxytryptamine type 2A receptor-induced currents by n-alcohols and anesthetics. 919 Aug 46

Modulation of [Ca2+]i in response to receptor activation is a critical determinant of vascular smooth muscle tone. In this study, we examined the effect of continuous stimulation of alpha 1-adrenoceptors with phenylephrine (PE) on [Ca2+]i in single pulmonary artery smooth muscle cells (PASMCs) cultured from explants of canine intrapulmonary artery. Fura 2-loaded PASMCs pretreated with propranolol (5 mumol/L) were continuously superfused with PE at 37 degrees C on the stage of an inverted fluorescence microscope, and [Ca2+]i was measured using a dual-wavelength spectrofluorometer. Resting values of [Ca2+]i were 96 +/- 4 nmol/L. PE (10 mumol/L) stimulated oscillations in [Ca2+]i at a frequency of 1.35 +/- 0.07/min, which reached a peak [Ca2+]i of 650 +/- 26 nmol/L (n = 69 cells). The oscillations lasted for > 30 minutes and were constant in amplitude and frequency. Both the amplitude and frequency of PE-induced [Ca2+]i oscillations increased in a dose-dependent (3 x 10(-8) to 10(-4) mol/L) manner. Pretreatment with the alpha 1-adrenoceptor antagonist prazosin (50 nmol/L) or removal of extracellular Ca2+ abolished the repetitive [Ca2+]i oscillations induced by PE. The voltage-operated Ca2+ channel blockers nifedipine (1 mumol/L) and verapamil (1 mumol/L) had no effect on the [Ca2+]i oscillations. In contrast, inhibition of phospholipase C with U73122 (10(-7) to 10(-5) mol/L) attenuated the oscillations in a dose-dependent fashion. The nonselective protein kinase inhibitor staurosporine (10(-9) to 10(-7) mol/L) had a minimal inhibitory effect on the oscillations. Caffeine (30 mmol/L) and thapsigargin (1 mumol/L) abolished the oscillations, whereas pretreatment with ryanodine (1 to 100 mumol/L) had no effect. In freshly dispersed PASMCs, PE (10 mumol/L) induced oscillations in [Ca2+]i similar to those observed in cultured cells, and patch-clamp experiments revealed oscillations in membrane potential. These results indicate that PE induces [Ca2+]i oscillations in PASMCs via stimulation of alpha 1-adrenoceptors coupled to phospholipase C activation. Voltage-operated Ca2+ channels and protein kinases are not required for the oscillations. The requirement for extracellular Ca2+ and intracellular Ca2+ stores indicates that both Ca2+ influx and intracellular Ca2+ release play a role in the maintenance of the oscillations.
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PMID:Phenylephrine-induced Ca2+ oscillations in canine pulmonary artery smooth muscle cells. 935 55

1Convulxin (Cvx) is a well-characterized platelet aggregating glycoprotein isolated from Crotalus durissus terrificus and C. d. cascavella venoms. In the present report we show that Cvx induces tyrosine phosphorylation of human platelet proteins, including phospholipase C-gamma 2 (PLC gamma 2), and also stimulates [3H]arachidonic acid ([3H]AA) mobilization, pleckstrin phosphorylation, and an increase in the cytosolic Ca2+ concentration ([Ca2+]in) due to both Ca2+ entry and internal Ca2+ mobilization. Staurosporine, a potent protein kinase inhibitor, and genistein, a specific inhibitor of protein tyrosine kinases (PTK), were used to evaluate the role of protein tyrosine phosphorylation (PTP) in the signal transduction evoked by Cvx. Staurosporine and genistein inhibited in a dose-dependent manner platelet aggregation induced by Cvx. Both inhibitors significantly blocked to near basal levels breakdown of phosphatidylinositol 4,5-bisphosphate from [myo-2-3H]inositol-labeled platelets and the production of [3H]AA metabolites from [3H]AA-labeled platelets after challenge with Cvx. Cvx provokes an increase in [Ca2+]in in Fura-2-loaded platelets that was abolished by concentrations of staurosporine which also inhibited Cvx-induced platelet aggregation. In addition, Cvx stimulates a rapid increase in tyrosine phosphorylation of human platelets proteins with molecular masses of 40, 72/74, 78/80, 105, 120, and 145 kDa, followed by dephosphorylation. Furthermore, Cvx stimulates a rapid tyrosyl phosphorylation of a 145-kDa molecular mass protein that was identified as PLC gamma 2. PTP induced by Cvx was not inhibited when platelets were stimulated in the presence of indomethacin, apyrase, EDTA, or RGDS peptide. These results indicate that PTP is chronologically proximal to Cvx binding to platelets, and is independent of aggregation or fibrinogen binding to the integrin alpha IIb beta 3. On the other hand, the dephosphorylation step is inhibited by RGDS peptide or EDTA, suggesting that integrin alpha IIb beta 3 is envolved in this step. The profile obtained with Cvx resembles that obtained in platelets adherent to an immobilized ligand, such as immobilized collagen, in which PTP is independent on integrin alpha IIb beta 3. Thus, we suggest that Cvx is an example of a protein with adhesion molecule-like properties; i.e., it is an adhesin. In conclusion, our results show that Cvx induces multiple signaling pathways in platelets via a PTK-dependent pathway involving PLC gamma 2 tyrosyl phosphorylation, with the subsequent platelet responses. Cvx is unique among platelet soluble agonists because under test tube stirring conditions it induces a PTP profile independently of integrin alpha IIb beta 3.
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PMID:Convulxin induces platelet activation by a tyrosine-kinase-dependent pathway and stimulates tyrosine phosphorylation of platelet proteins, including PLC gamma 2, independently of integrin alpha IIb beta 3. 960 58

In membranes of the rat frontal cortex, acetylcholine (ACh) and other cholinergic agonists were found to potentiate the stimulation of adenylyl cyclase activity elicited by corticotropin-releasing hormone (CRH). Oxotremorine-M, carbachol and methacholine were as effective as ACh, whereas oxotremorine and arecoline were much less effective. The facilitating effect of Ach was potently blocked by the M1 antagonists R-trihexyphenidyl, telenzepine and pirenzepine and by the M3 antagonists hexahydro-sila-difenidol and p-fluorohexahydro-sila-difenidol, whereas the M2 and M4 antagonists himbacine, methoctramine, AF-DX 116 and AQ-RA 741 were less potent. The mamba venom toxin MT-1, which binds with high affinity to M1 receptors, was also a potent blocker. The pharmacological profile of the muscarinic potentiation of CRH receptor activity was markedly different from that displayed by the muscarinic inhibition of forskolin-stimulated adenylyl cyclase, which could be detected in the same membrane preparations. Moreover, the intracerebral injection of pertussis toxin impaired the muscarinic inhibition of cyclic AMP formation and reduced the Ach stimulation of [35S]GTPgammaS binding to membrane G proteins but failed to affect the facilitating effect on CRH receptor activity. The latter response was also insensitive to the phospholipase C inhibitor U-73122, the protein kinase inhibitor staurosporine and to the inhibitors of arachidonic acid metabolism indomethacin and nordihydroguaiaretic acid. These data demonstrate that in the rat frontal cortex, muscarinic receptors of the M1 subtype potentiate CRH transmission by interacting with pertussis toxin-insensitive G proteins.
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PMID:Identification and characterization of muscarinic receptors potentiating the stimulation of adenylyl cyclase activity by corticotropin-releasing hormone in membranes of rat frontal cortex. 969 30

1. In this study, the underlying mechanism of stimulation of respiratory burst by kazinol B, a natural isoprenylated flavan, in rat neutrophils in vitro was investigated. 2. Kazinol B concentration-dependently stimulated the superoxide anion (O2*-) generation, with a lag but transient activation profile, in neutrophils but not in a cell-free system. The maximum response (13.2+/-1.4 nmol O2*- 10 min(-1) per 10(6) cells) was observed at 10 microM kazinol B. 3. Pretreatment of neutrophils with phorbol 12-myristate 13-acetate (PMA) or formylmethionyl-leucyl-phenylalanine (fMLP) significantly enhanced the O2*- generation following the subsequent stimulation of cells with kazinol B. 4. Cells pretreated with EGTA or a protein kinase inhibitor staurosporine effectively attenuated the kazinol B-induced O2*- generation. However, a p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 and a phosphoinositide 3-kinase (PI3K) inhibitor wortmannin had no effect on the kazinol B-induced response. 5. Kazinol B significantly stimulated [Ca2+]i elevation in neutrophils, with a lag and slow rate of rise activation profile, and this response was attenuated by a phospholipase C (PLC) inhibitor U73122. Kazinol B also stimulated the inositol bis- and trisphosphate (IP2 and IP3) formation with a 1 min lag time. 6. The membrane-associated PKC-alpha and PKC-theta but not PKC-iota were increased following the stimulation of neutrophils with kazinol B. It was more rapid and sensitive in the activation of PKC-theta than PKC-alpha by kazinol B. Kazinol B partially inhibited the [3H]phorbol 12,13-dibutyrate ([3H]PDB) binding to the neutrophil cytosolic PKC. 7. Neither the cellular mass of phosphatidic acid (PA) and phosphatidylethanol (PEt), in the presence of ethanol, nor the protein tyrosine phosphorylation were stimulated by kazinol B. In addition, the kazinol B-induced O2*- generation remained relatively unchanged in cells pretreated with ethanol or a tyrosine kinase inhibitor genistein. 8. Collectively, these results indicate that the stimulation of the respiratory burst by kazinol B is probably mediated by the synergism of PKC activation and [Ca2+]i elevation in rat neutrophils.
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PMID:The signal transduction mechanism involved in kazinol B-stimulated superoxide anion generation in rat neutrophils. 980 35

Chronic treatment with basic fibroblast growth factor (bFGF) increases the expression of functional L-type voltage-dependent Ca2+ channels (VDCCs) in fetal rat hippocampal neurons. We investigated the intracellular signaling mechanisms involved in this effect, using high K+ depolarization-induced elevation of intracellular Ca2+ concentrations as a measure. Genistein, a protein tyrosine kinase inhibitor, significantly attenuated the effect of bFGF. The effect of bFGF was also diminished by concurrent application of a Ras inactivator, N-acetyl-S-farnesyl-l-cysteine. In contrast, a phospholipase C inhibitor U73122, a phosphatidylinositol-3 kinase inhibitor wortmannin, Li+ which inhibits inositol phospholipid turnover, or a protein kinase inhibitor calphostin C did not inhibit the effect of bFGF. Phorbol 12-myristate 13-acetate, a protein kinase C activator, did not mimic the effect of bFGF. On the other hand, an adenylyl cyclase activator forskolin and a cyclic AMP analog 8-Br-cyclic AMP markedly attenuated the effect of bFGF, which indicates the presence of a cyclic AMP-mediated negative regulatory mechanism, possibly the interference of Ras-Raf interaction. These results suggest that Ras-mediated signal transduction is required for the enhancement by bFGF of VDCC responses in hippocampal neurons.
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PMID:A potential role of Ras-mediated signal transduction for the enhancement of depolarization-induced Ca2+ responses in hippocampal neurons by basic fibroblast growth factor. 983 95

Both cAMP- and cGMP-dependent protein kinases inhibit agonist-stimulated phospholipase C-beta (PLC-beta) activity and inositol 1,4,5-trisphosphate-dependent Ca2+ release in vascular and visceral smooth muscle. In smooth muscle of the intestinal longitudinal layer, however, the initial steps in Ca2+ mobilization involve activation of cytosolic PLA2 (cPLA2) and arachidonic acid (AA)-dependent stimulation of Ca2+ influx. The present study examined whether cAMP- and cGMP-dependent protein kinases are capable of regulating these processes also. Agents that activated cAMP-dependent protein kinase (5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole 3',5'-cyclic monophosphothioate (Sp-isomer) and isoproterenol), cGMP-dependent protein kinase (8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate and Na nitroprusside), or both kinases (vasoactive intestinal peptide and isoproterenol >1 microM) induced phosphorylation of cPLA2 and inhibition of agonist-stimulated cPLA2 activity. Phosphorylation and inhibition of cPLA2 activity by cAMP- and cGMP-dependent protein kinases were blocked by the corresponding selective inhibitors (cAMP-dependent protein kinase, N-[2(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide hydrochloride (H-89) and myristoylated protein kinase inhibitor () amide; cGMP-dependent protein kinase, (8R,9S, 11S)-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8, 11-epoxy-1H,8H,11H,-2,7b,11a-trizadizobenzo(a,g)cycloocta(c, d, e)-trinden-1-one (KT-5823)). In contrast, AA-stimulated Ca2+ influx was inhibited by agents that activated cGMP-dependent protein kinase only; the inhibition was selectively blocked by KT-5823. The study provides the first evidence of inhibitory phosphorylation of cPLA2 in vivo by cAMP- and cGMP-dependent protein kinases. Inhibition of cPLA2 activity and AA-induced Ca2+ influx partly account for the ability of cAMP-dependent protein kinase and/or cGMP-dependent protein kinase to cause relaxation. Their importance resides in their location at the inception of the Ca2+ signaling cascade.
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PMID:Differential regulation of phospholipase A2 (PLA2)-dependent Ca2+ signaling in smooth muscle by cAMP- and cGMP-dependent protein kinases. Inhibitory phosphorylation of PLA2 by cyclic nucleotide-dependent protein kinases. 985 21


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