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 cystic fibrosis transmembrane regulator (CFTR) is a Cl- channel regulated by adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase A. A cAMP-independent activation has been recently shown for the protein tyrosine kinase inhibitor genistein in CFTR-transfected NIH/3T3 fibroblasts. We further studied the role of genistein on Cl- secretion in HT-29/B6 and T84 colonic epithelial cells, which express native CFTR in their apical membranes. Transepithelial Cl- secretion was more effectively stimulated in T84 cells when compared with HT-29/B6 cells by mucosal perfusion with 50 microM genistein. Genistein, like the cAMP agonist forskolin, stimulated CFTR activity in cell-attached patches of single cells with similar slope conductances of 8.5 +/- 0.5 and 9.2 +/- 0.3 pS, respectively. Monolayers in Ussing chambers were basolaterally permeabilized with the pore former alpha-toxin, and gradient-driven Cl- current across the apical membrane (ICl) was measured. ICl was stimulated by serosal (i.e., cytosolic) cAMP (half-maximal stimulatory concentration = 9.8 +/- 1.9 microM). In the presence of cAMP (> 5 microM), subsequent mucosal, but not serosal, addition of genistein further increased Icl by approximately 16%; in the absence of cytosolic cAMP, genistein had no effect on ICl. The inactive analogue daidzein had no effect. When cAMP agonists were removed in the continued presence of genistein, ICl remained elevated in both permeabilized and intact monolayers as well as in cell-attached patches of single cells. In addition, genistein blocked K- currents across the basolateral membrane in apically amphotericin B-permeabilized monolayers (half maximal inhibitory concentration = 44.2 +/- 8.1 microM). Therefore, in intact epithelia, the overall secretory response to genistein is composed of stimulatory effects on the apical CFTR and inhibitory effects on the basolateral K+ conductance. We propose that genistein blocks a phosphatase, which regulates CFTR during cAMP-dependent stimulation.
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PMID:Alternate stimulation of apical CFTR by genistein in epithelia. 877 53

A cDNA encoding a mouse B2 bradykinin (BK) receptor was stably transfected in Chinese hamster ovary (CHO) cells. In two resulting transformants, mouse B2 BK receptor was found to induce a twofold elevation in the inositol-1,4,5-trisphosphate level. In a pertussis toxin-insensitive manner, BK also produced a biphasic increase in the intracellular Ca2+ concentration ([Ca2+]i). The initial elevation in [Ca2+]i was abolished by thapsigargin pretreatment in Ca(2+)-free medium. The second phase was dependent on external Ca2+. The BK/inositol trisphosphate and thapsigargin-sensitive Ca2+ stores required extracellular Ca2+ for refilling. Ca2+ influx induced by BK and thapsigargin was confirmed by Mn2+ entry through Ca2+ influx pathways producing Mn2+ quenching. Genistein, a tyrosine kinase inhibitor, partially decreased the BK-induced [Ca2+]i increase during the sustained phase and the rate of Mn2+ entry. BK had essentially no effect on the intracellular cyclic AMP level. The results suggest that the mouse B2 BK receptor couples to phospholipase C in CHO cells and that its activation results in biphasic [Ca2+]i increases, by mobilization of intracellular Ca2+ and store-depletion-mediated Ca2+ influx, the latter of which is tyrosine phosphorylation dependent.
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PMID:Ca2+ release and Ca2+ influx in Chinese hamster ovary cells expressing the cloned mouse B2 bradykinin receptor: tyrosine kinase inhibitor-sensitive and- insensitive processes. 903 Feb 5

PGF2alpha stimulates the proliferation of clonal osteoblastic MC3T3-E1 cells via PGF2alpha receptor linked to phospholipase C activation. To elucidate intracellular events elicited by this receptor, we examined the effects of PGF2alpha on tyrosine phosphorylation and mitogen-activated protein kinase (MAPK) activity in MC3T3-E1 cells. PGF2alpha rapidly raised the level of phosphotyrosine of cellular proteins with Mr values of 62, 68, 72, 76, 82, 125, and 150 kDa. This PGF2alpha-induced tyrosine phosphorylation of proteins (except for pp62) was blocked by down-regulating protein kinase C (PKC) by 12-O-tetradecanoylphorbol 13-acetate pretreatment and by GF 109203X, a potent specific PKC inhibitor. The addition of PGF2alpha also transiently activated MAPK in the same range of concentrations that stimulated tyrosine phosphorylation. In addition, PGF2alpha augmented the MAPK kinase kinase activity of Raf-1, whereas basal activity of MAPK/extracellular signal-regulated protein kinase kinase was less than that of Raf-1 and was little affected by PGF2alpha. Like the tyrosine phosphorylation, these activations of Raf-1 and MAPK activities were reduced by inhibition and down-regulation of PKC. Genistein, a potent inhibitor of tyrosine kinases, did not block the Raf-1 induced by PGF2alpha, indicating a tyrosine kinase-independent pathway for Raf-1 activation. However, the tyrosine kinase inhibitor partially inhibited the MAPK activity, suggesting an involvement of another Raf-1-independent kinase cascade for activation of MAPK by PGF2alpha. Fluprostenol, a specific agonist of PGF2alpha receptor, mimicked the actions of PGF2alpha consistent with a PGF2alpha receptor pathway. Thus, the action of PGF2alpha on osteoblastic MC3T3-E1 cells appears to involve a single receptor that uses diverse interacting signal transduction systems.
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PMID:Prostaglandin F2alpha stimulates tyrosine phosphorylation and mitogen-activated protein kinase in osteoblastic MC3T3-E1 cells via protein kinase C activation. 911 74

We studied the role of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel as an HCO3- conductor during adenosine 3',5'-cyclic monophosphate (cAMP)-dependent regulation in human airway epithelial cell lines. HCO3- or Cl- currents across the apical membrane were measured in the presence of an HCO3- or Cl- gradient under short-circuit conditions in intact and alpha-toxin-permeabilized monolayers, which allowed manipulation of the intracellular regulators cAMP and ATP. CFTR as the current carrier for HCO3- was identified by 1) stimulation by cAMP, 2) ATP dependence, 3) blocker sensitivity, 4) stimulation by genistein, and 5) lack of stimulation in CF epithelia bearing mutated delta F508 CFTR. In pulmonary alpha-toxin-permeabilized Calu-3 monolayers, cytosolic addition of 100 microM cAMP stimulated apical HCO3- currents from -9.4 +/- 1.6 to -31.1 +/- 3.9 microA/cm2 (n = 18), and apical Cl- currents increased from -54.1 +/- 7.1 to -203.2 +/- 15.4 microA/cm2 (n = 27). Average relative permselectivity for HCO3- vs. Cl- was approximately 15%. Absence of cytosolic ATP resulted in loss of cAMP stimulation of HCO3- and Cl- currents. Genistein (50 microM), which has been proposed to inhibit phosphatases controlling apical CFTR, as well as the alkaline phosphatase inhibitor (-)-p-bromotetramisole (1 mM) further activated cAMP-stimulated HCO3- and Cl- currents. Activated currents remained stimulated on removal of cAMP, suggesting inhibition of a protein phosphatase by genistein and bromotetramisole. The Cl- channel blockers glibenclamide (300 microM) and N-phenylanthranilic acid (5 mM), but not 4,4'-dinitro-2,2'-stilbenedisulfonic acid (100 microM), inhibited cAMP- and genistein-stimulated HCO3- and Cl- currents. Blocker effects were absent in human CF tracheal cells homozygous for the delta F508 mutation of CFTR (CFT1); Cl- and HCO3- currents were rescued in CFT1 cells recombinantly expressing wild-type CFTR. Thus CFTR functions as a HCO3- and Cl- conductor, and genistein and bromotetramisole maximize CFTR activity in airway epithelial cells.
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PMID:cAMP and genistein stimulate HCO3- conductance through CFTR in human airway epithelia. 914 51

Zooxanthellatoxin-A (ZT-A), a polyhydroxypolyene isolated from a symbiotic dinoflagellate Symbiodinium sp., caused thromboxane A2-(TXA2) dependent and genistein-sensitive aggregation in rabbit platelets. Our study was performed to clarify the mechanism of the action of ZT-A. ZT-A caused an increase in tyrosine phosphorylation of 42-kDa protein, which is defined as p42 mitogen-activated protein kinase (MAPK) by immunoprecipitation. Although indomethacin (10 microM) completely inhibited ZT-A-induced TXB2 release, it partially inhibited the MAPK activation. The remained MAPK activation was completely inhibited by genistein (50 microM). Genistein (50 microM), by itself, abolished TXB2 release induced by ZT-A. ZT-A (2 microM) stimulated liberation of arachidonic acid and the subsequent metabolites such as TXB2 and 12-hydroperoxyeicosatetraenoic acid. However, ZT-A-stimulated phosphoinositide hydrolysis which was due to an increase in tyrosine phosphorylation of phospholipase C-(PLC)gamma2. The phosphorylation of PLC-gamma2 and the phosphoinositide hydrolysis were also partially inhibited by indomethacin (10 microM), and were abolished by a combined treatment of indomethacin (10 microM) and genistein (50 microM). ZT-A- (2 microM) induced MAPK activation in the presence of indomethacin (10 microM) was concentration-dependently inhibited by staurosporine and calphostin C, protein kinase C inhibitors. PD98059 (50 microM), a MAPK kinase inhibitor, also inhibited ZT-A-induced TXB2 release. Depletion of external Ca++ abolished ZT-A- (2 microM) induced MAPK activation, phosphoinositide hydrolysis, arachidonic acid liberation and TXB2 release. These results suggest that ZT-A stimulates a protein tyrosine kinase in the presence of external Ca++, resulting in the activation of MAPK probably via PLC-gamma2 and protein kinase C. The MAPK stimulated a liberation of arachidonic acid that is rapidly converted to TXA2. The released TXA2 causes aggregation accompanied with second stimulation of MAPK cascade.
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PMID:Involvement of phospholipase C-gamma2 in activation of mitogen-activated protein kinase and phospholipase A2 by zooxanthellatoxin-A in rabbit platelets. 922 92

We previously reported that basic fibroblast growth factor (bFGF) stimulates both phospholipases C and D via independent pathways in osteoblastlike MC3T3-E1 cells. In this study, we investigated the effect of bFGF on interleukin-6 (IL-6) synthesis in these cells. bFGF stimulated the IL-6 synthesis dose-dependently in the range between 1 and 30 ng/ml. The depletion of extracellular Ca2+ by EGTA suppressed the bFGF-induced IL-6 synthesis. TMB-8, an inhibitor of intracellular Ca2+ mobilization, also inhibited the IL-6 synthesis by bFGF. bFGF stimulated the Ca2+ influx from extracellular space. Genistein, a tyrosine kinase inhibitor, suppressed the bFGF-induced Ca2+ influx. Staurosporine, an inhibitor for protein kinases, enhanced the bFGF-induced IL-6 synthesis. Calphostin C, a highly potent and specific inhibitor for protein kinase C (PKC), also enhanced the IL-6 synthesis by bFGF. The bFGF-induced IL-6 synthesis was amplified in PKC down-regulated cells. U-73122, a phospholipase C inhibitor, enhanced the bFGF-induced IL-6 synthesis. Propranolol, a phosphatidic acid phosphohydrolase inhibitor, also enhanced the IL-6 synthesis by bFGF. These results strongly suggest that bFGF stimulates IL-6 synthesis, which depends on intracellular Ca2+ mobilization in osteoblastlike cells, and that the IL-6 synthesis by bFGF is autoregulated due to PKC activation.
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PMID:Basic fibroblast growth factor induces interleukin-6 synthesis in osteoblasts: autoregulation by protein kinase C. 937 29

Stimulation of the respiratory burst of neutrophil leukocytes with chemotactic agonists requires two concomitant signal transduction pathways. One is calcium dependent and leads to activation of phospholipase C, the other is calcium independent but sensitive to the fungal metabolite wortmannin, a specific inhibitor of phosphatidylinositide 3-kinase (PI 3-kinase). Two isoforms of PI 3-kinase have been characterized in neutrophils, the p85/p110 PI 3-kinase alpha and the p101/p120 PI 3-kinase gamma. The relative contribution of the two PI 3-kinases in mediating chemoattractant-stimulated superoxide production and exocytosis in neutrophils in unclear. Here, we report that the protein tyrosine kinase inhibitor genistein markedly attenuates chemoattractant-stimulated phosphatidylinositol (3,4,5)-trisphosphate (PIP3) formation in neutrophils. PI 3-kinase activity in untreated cells is bimodal showing a maximum production after 10-15 sec that protracts with a lower PIP3 formation for approximately 2 min and returns to basal levels after 2-3 min. Genistein at 100 microM strongly inhibits PIP3 elevation and the fMet-Leu-Phe-stimulated respiratory burst. The activity of purified PI 3-kinase, however, is not altered in the presence of genistein, suggesting that the genistein-sensitive intermediate is located between the G-protein-coupled receptor and PI 3-kinase. Expression of a dominant negative form of PI 3-kinase alpha in GM-1/CXCR1 cells, a promyelolocytic cell line transfected with the G-protein-coupled receptors CXCR1, considerably reduces IL-8-stimulated PIP3 formation. The present observations suggest that in phagocytes stimulated with agonists of G-protein-coupled receptors the bulk of PIP3 is generated by PI 3-kinase alpha, which is activated through a genistein-sensitive target, presumably a protein tyrosine kinase.
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PMID:G-protein coupled receptor-mediated activation of PI 3-kinase in neutrophils. 970 65

In opossum kidney (OK) cells, L-dihydroxyphenylalanine (10 microM) raised dopamine to 10 nM and inhibited Na-inorganic phosphate (Pi) uptake 20% (P = 0.001). Inhibition was completely blocked by carbidopa or SCH23390. Dopamine (1 microM) inhibited uptake 55% (half-maximal inhibition, 0.03 microM). Fenoldopam (0.1 microM, DA1 agonist) inhibited uptake 45 +/- 2%. DA1 antagonists (SKF83566 and SCH23390), but not DA2-antagonist (sulpiride), blocked dopamine inhibition. Quinpirole (DA2 agonist) did not modify Pi uptake. Bisindolylmaleimide (10 microM), a protein kinase C inhibitor, blocked inhibition of Pi uptake by phorbol ester but had no effect on the response to dopamine. Dopamine inhibited Pi uptake in cells that had been exposed to phorbol ester for 18 to 24 h. Dopamine inhibition was not reduced by 1 microM U73,122 but was reduced 20% by 10 microM, which is 10 times the concentration reported to completely inhibit phospholipase C in OK cells. Adenylate cyclase inhibitors SQ 22536 (100 microM) and 2,5-dideoxyadenosine (100 microM) reduced dopamine-stimulated cAMP production, but not dopamine inhibition of Pi uptake. Rp-cAMPS counteracted the inhibition of Pi uptake by Sp-cAMPS but had no effect on the dopamine response. H-89 inhibited dopamine-stimulated protein kinase A activity, but neither H-89 nor H-9 alone or with bisindolylmaleimide altered dopamine inhibition of Pi uptake. Genistein and herbimycin A (tyrosine kinase inhibitors) reduced Pi uptake. However, dopamine, a benzoquinone like several tyrosine kinase inhibitors, did not inhibit tyrosine kinase activity. Thus, dopamine inhibited Pi uptake in this OK cell clone by activating a G protein-linked pathway that operates independently from adenylyl cyclase, protein kinase A, protein kinase C, and protein tyrosine kinase.
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PMID:Does dopamine use several signal pathways to inhibit Na-Pi transport in OK cells? 972 68

The aim of these studies was to examine the involvement of tyrosine phosphorylation in the signal transduction pathways and secretory events that are promoted by receptor agonists acting on rat parotid acinar cells. Fluid secretion by parotid acinar cells is initiated by the binding of neurotransmitters to GTP(G)-protein-coupled receptors that are linked to phospholipase C, which hydrolyzes phosphatidlyinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate. Although growth factors produce large changes in tyrosine phosphorylation of multiple proteins involved in proliferation and other cellular processes, tyrosine phosphorylation is not considered to be a general phenomenon of G-protein-coupled receptor activation. However, our results shown that carbachol (a muscarinic acetylcholine receptor agonist), and ligands to other phospholipase C-linked receptors, promoted a rapid increase in the tyrosine phosphorylation of protein kinase Cdelta (PKCdelta), a member of the PKC family of proteins. Phorbol 12-myristate 13-acetate, which binds to the site on PKCdelta to which the endogenous activator sn-1,2-diacylglycerol binds, also increased the tyrosine phosphorylation of PKCdelta. Genistein and staurosporine, two protein kinase inhibitors, blocked the tyrosine phosphorylation of this protein. Thus, PKCdelta becomes tyrosine phosphorylated in response to receptor activation, and this event appears to involve both diacylglycerol production and protein tyrosine kinase activity. This may contribute to early physiological events, including alterations in fluid secretion, that are initiated by neurotransmitters acting on the parotid salivary gland.
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PMID:Involvement of protein kinases and phosphatases in tyrosine phosphorylation of PKCdelta in rat parotid acinar cells exposed to secretory stimuli. 982 17

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


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