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 demonstrated that stimulation of cultured rat neonatal cardiomyocytes by endothelin-1 (ET-1) induces rapid activation of phospholipase C-beta (PLC-beta), accompanied by transient expression of proto-oncogenes and subsequent development of hypertrophy and characteristic phenotypic changes. In the present study we examined the ET-1-induced hypertrophic response in relation to the initial signaling by phospholipase D (PLD) and protein kinase C (PKC). ET-1 (10(-8) M) induced hypertrophy after 48 h, as judged by protein/DNA ratio. The formation (0.5 h) of 14C-labeled phosphatidylethanol ([14C]PEth) in the presence of exogenous ethanol (0.5%) in [14C]palmitate prelabeled cells, which reflects the PLD activity, was increased 1.9- and 5.6-fold by ET-1 and phorbolester (PMA, 10(-6) M), respectively. The translocation of PKC isoforms from the cytosol to the membrane fraction was examined by immunoblot analysis using specific antibodies for PKC-alpha and -epsilon. ET-1 caused a rapid (within 15 s) and sustained disappearance of PKC-epsilon but not of PKC-alpha, from the cytosol. The translocation of PKC-epsilon to the membrane fraction was just detectable. However, PMA (10(-7) M) showed a rapid, sustained, and clearly detectable translocation of PKC-alpha and PKC-epsilon. The results indicate that the ET-1-induced development of hypertrophy via activation of distinct PKC isoenzymes may be initiated not only by PLC-beta but also by PLD signaling.
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PMID:Endothelin-1-induced phospholipase C-beta and D and protein kinase C isoenzyme signaling leading to hypertrophy in rat cardiomyocytes. 858 31

In estrogen-treated rat myometrium, endothelin-1 (ET-1) activated both the phospholipase C (PLC) which degrades PtdInsP2, resulting in an increased accumulation of inositol phosphates, and the phospholipase D pathway (PLD) as evidenced in the presence of butanol by an increased production of phosphatidylbutanol (PBut). Both ET-1 effects displayed similar concentration dependencies (EC50 50 nM) and were mediated by ET(A) receptors in that they were antagonized by BQ123 and were elicited by ET-3 with a rank order of potency ET-1 >> ET-3. Bombesin, another activator of the PLC/PtdInsP2 pathway, also increased PBut accumulation. Enhanced production of PBut could also be observed with the Ca2+ ionophore ionomycin and the phorbol ester PMA, an activator of protein kinase C, suggesting a potential contribution of the PLC/PtdInsP2 pathway in ET-1 induced PLD activity.
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PMID:ETA receptors mediate activation of phospholipases C and D in rat myometrium. 858 97

Heat-stable antigen (HSA), expressed by various antigen-presenting cells (APC), has been described as a costimulatory molecule for CD4+ T cells. Recently, we observed that HSA also serves as an important costimulatory molecule on epidermal Langerhans cells (LC). During these studies, low levels of HSA staining were also detected on normal murine keratinocytes (KC). To investigate whether HSA also is involved in T-cell activation by KC, normal murine KC or the spontaneously transformed KC cell-line PAM 212 were treated with PDB or PMA to induce HSA-expression. FACS analyses showed induction of HSA expression on normal murine KC, as well as PAM 212 cells. In functional assays PDB or PMA-treated normal or transformed KC were far more potent inducers of primary allogeneic T-cell responses than untreated KC. Addition of anti-HSA-specific mAb 20C9 specifically inhibited the costimulatory activity of KC, an effect that was even more pronounced when CTLA-4Ig was added to the cultures. Cleavage of HSA on KC surfaces by a phosphoinositol-specific phospholipase C (PI-PLC) also significantly inhibited the costimulatory capacity of KC for naive CD4+ T cells. In aggregate, our data indicate that expression of HSA on activated KC contributes to the capacity of these cells to induce proliferation of allogeneic T cells.
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PMID:Heat-stable antigen is expressed by murine keratinocytes and delivers costimulatory signals in T-cell activation. 858 19

Many cell surface proteins are anchored into the cell membrane by glycosylphosphatidylinositol (GPI), among those a recently discovered arginine-specific mono-ADP-ribosyltransferase on cytotoxic T cells (CTL). This enzyme transfers ADP-ribose to cell surface proteins resulting in inhibition of cytotoxic and proliferative activity. Here we report that ADP-ribosyltransferase is released in active forms by crosslinking CD3, exposure to Il-2 or PMA stimulation. Release of transferase is specific, as another GPI-anchored protein, Thy-1 is not released. Transferase molecules released by cell activation are indistinguishable in size from molecules released by phospholipase C, suggesting that the release mechanism acts close to or within the GPI anchor. Protease inhibitors fail to inhibit transferase release with exception of 1,10-phenanthroline and its 4,7-diphenyl derivative. This suggests that the release mechanism acts on the cell surface but does not discriminate between action of a metalloprotease or phospholipase D. Release of transferase is shown to be rapid, it is not suppressed by monensin or brefeldin A and independent of serum phospholipase D, consistent with a mechanism acting on the cell surface. Transferase expression is shown to be dependent on the cell activation stage. In CTL clones, the transferase is demonstrable as a phospholipase C releasable molecule at early but not later stages of Ag specific activation.
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PMID:Release of a glycosylphosphatidylinositol-anchored ADP-ribosyltransferase from cytotoxic T cells upon activation. 859 99

The anabolic effect of parathyroid hormone (PTH) on bone is partly due to a stimulation of osteoblast proliferation. The PTH signal is transduced by the pathways of adenylyl cyclase (AC)/protein kinase (PK) A and phospholipase C/PKC/Ca++. There is still uncertainty about the relative contribution of the two pathways to the proliferative effects of the hormone. In our study, PTH(1-34), AC/PKA agonists, and phorbol 12-myristate-13-acetate (PMA, a PKC activator) stimulated cell proliferation in cultured mouse calvariae. In isolated osteoblasts, only PMA stimulated proliferation, whereas AC/PKA agonists and PTH(1-34) inhibited it. As already known, PTH in the presence of supramaximal concentrations of transforming growth factor-beta (TGF-beta) stimulated osteoblast growth; under these same conditions, AC/PKA agonists reproduced the stimulatory effect of PTH(1-34), whereas PMA became inhibitory. PTH(1-31), which stimulates AC without affecting PKC, acted similarly to the fully active PTH(1-34) in both calvaria and isolated osteoblasts. On the contrary, midregion fragments that activate only PKC stimulated calvaria cell proliferation faintly in comparison with PTH(1-34); no effect was seen in osteoblasts, either with or without TGF-beta. Our study shows that the effects of PTH on proliferation can be mimicked by agonists of the AC/cAMP pathway. Although PMA is indeed able to stimulate cell growth in tissue explants, its effects on isolated osteoblasts markedly diverge from those of PTH. We conclude that activation of the AC/PKA pathway is the main component of the proliferative effects of PTH.
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PMID:Effects of parathyroid hormone and agonists of the adenylyl cyclase and protein kinase C pathways on bone cell proliferation. 871 38

Gonadotropin-releasing hormone acts via G-protein coupled receptors to stimulate polyphosphoinositide-specific phospholipase C (PIC) with consequent elevation of cytosolic Ca2+ and activation of protein kinase C (PKC). Whereas Ca2+ is known to mediate stimulation of exocytotic gonadotropin release by GnRH, the identity of the PKC isoenzymes activated by GnRH and their physiological role in gonadotropes are poorly understood. In many systems translocation of PKC (from cytosolic to particulate fractions of cellular homogenates) has been taken as evidence of hormonal activation of PKC and down regulation of PKC (by prolonged treatment with PKC-activating phorbol esters) has been used extensively to investigate the role of PKC in hormone action. Here we have assessed the influence of GnRH and phorbol esters on translocation and down regulation of PKC isoenzymes identified by Western blotting with isoenzyme-specific antibodies in alpha T3-1 cells (a gonadotrope-derived cell line). These cells were found to posses PKCs alpha, epsilon and zeta but not beta, delta (present in rat pituitaries) or gamma (present in rat brains). In short-term stimulations (10 min), the PKC-activating phorbol esters, PMA and PDBu, caused concentration-dependent increases in the proportion of PKC alpha and PKC epsilon recovered from the particulate fraction of alpha T3-1 cells, but did not induce measurable translocation of PKC zeta. The inactive phorbol ester 4 alpha PDBu did not cause translocation of any of these isoenzymes. GnRH treatment induced a concentration-dependent increase in the proportion of particulate PKC epsilon and PKC zeta but had no measurable effect on PKC alpha translocation. In longer incubations (6-48 h) GnRH failed to cause measurable down-regulation of these isoenzymes whereas PMA treatment led to a clear down regulation of PKCs alpha and epsilon (albeit with different kinetics). The data demonstrate the differential activation and down regulation of PKC isoenzymes by GnRH versus PMA, which are clearly pertinent to the design of experiments intended to address the role of such isoenzymes in GnRH action. Moreover, they provide the first demonstration of hormonal regulation of an atypical PKC isoenzyme (PKC zeta) in pituitary cells.
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PMID:Selective translocation of non-conventional protein kinase C isoenzymes by gonadotropin-releasing hormone (GnRH) in the gonadotrope-derived alpha T3-1 cell line. 873 96

There is now clear evidence that receptor-dependent phospholipase D is present in myocardium. This novel signal transduction pathway provides an alternative source of 1,2-diacylglycerol, which activates isoforms of protein kinase C. The members of the protein kinase C family respond differently to various combinations of Ca2+, phosphatidylserine, molecular species of 1,2-diacylglycerol and other membrane phospholipid metabolites including free fatty acids. Protein kinase C isozymes are responsible for phosphorylation of specific cardiac substrate proteins that may be involved in regulation of cardiac contractility, hypertrophic growth, gene expression, ischemic preconditioning and electrophysiological changes. The initial product of phospholipase D, phosphatidic acid, may also have a second messenger role. As in other tissues, the question how the activity of phospholipase D is controlled by agonists in myocardium is controversial. Agonists, such as endothelin-1, atrial natriuretic factor and angiotensin II that are shown to activate phospholipase D, also potently stimulate phospholipase C-beta in myocardium. PMA stimulation of protein kinase C inactivates phospholipase C and strongly activates phospholipase D and this is probably a major mechanism by which agonists that promote phosphatidyl-4,5-bisphosphate hydrolysis secondary activate phosphatidylcholine-hydrolysis. On the other hand, one group has postulated that formation of phosphatidic acid secondary activates phosphatidyl-4,5-bisphosphate hydrolysis in cardiomyocytes. Whether GTP-binding proteins directly control phospholipase D is not clearly established in myocardium. Phospholipase D activation may also be mediated by an increase in cytosolic free Ca2+ or by tyrosine-phosphorylation.
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PMID:Regulation and functional significance of phospholipase D in myocardium. 873 27

Adhesion to solid substrata has been shown to increase intracellular pH (pH(i)) of fibroblasts and of other cells (FEBS Lett. (1988) 234, 449-450; Proc. Natl. Acad. Sci. USA (1989) 86, 4525-4529; J. Biol. Chem. (1990) 265, 1327-1332; Exp. Cell Res. (1992) 200, 211-214; FEBS Lett. (1995) 374, 17-20). We have found that the inhibitors of PLA2, 4-bromophenacyl bromide and manoalide, completely blocked the increase of pH(i) and spreading of neutrophils upon adhesion to solid substrata. Inhibition of phospholipase C with neomycin or removal of extracellular Ca2+ affects neither neutrophil spreading nor their pH(i). Inhibition of PKC with H-7 or staurosporin increased pH(i). PMA, an activator of PKC, dramatically decreased pH(i) but did not impair the spreading of neutrophils. The effect of arachidonic acid, a product of PLA2 activity, on neutrophil pH(i) and spreading was similar to that of PMA. H-7, an inhibitor of PKC, partially blocked the effect of arachidonic acid (AA) on pH(i). BW755C, an inhibitor of AA metabolism by cyclooxygenase or lipoxygenase, affected neither the pH(i) nor cell spreading. We propose that the increase of pH(i) upon neutrophil adhesion is mediated by PLA2 activity, while PKC decreased pH(i). AA produced by PLA2 activates PKC, thus forming a feedback regulation of pH(i).
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PMID:Regulation of intracellular pH by phospholipase A2 and protein kinase C upon neutrophil adhesion to solid substrata. 880 38

We have recently described that endothelins-1 to -3 equipotently inhibit cAMP stimulated renin secretion from cultured mouse juxtaglomerular cells by a process involving phospholipase C activation. This study examined the influence of endothelin-2 on renin gene expression in renal juxtaglomerular cells. To this end we semiquantitated renin mRNA levels by competitive RT-PCR in primary cultures of mouse renal juxtaglomerular cells after 20 hours of incubation. We found that endothelin-2 (0.1 to 100 nmol/liter) did not change basal renin gene expression. The adenylate cyclase activator forskolin (3 mumol/ liter) increased renin mRNA levels to 400% of the controls and this stimulation was dose-dependently attenuated by ET-2 to 250% of the control value. The effect of ET-2 was mimicked by the ETB-receptor agonist sarafotoxin S6c. The kinase inhibitor staurosporine (100 nmol/ liter) increased renin secretion and renin mRNA levels. Combination of staurosporine with forskolin produced the same effects on renin secretion and renin mRNA levels as did staurosporine alone. In the presence of both forskolin and staurosporine ET-2 had no significant effect on renin secretion and renin gene expression. The phorbol ester PMA (30 nmol/ liter), which was used to stimulate protein kinase C activity, attenuated cAMP stimulated renin secretion and renin mRNA levels. Lowering the extracellular concentration of calcium by the addition of 1 mmol/liter EGTA did not inhibit the effect of ET-2 on cAMP induced renin secretion and renin gene expression. These findings suggest that endothelins inhibit cAMP stimulated renin gene expression by an event that is mediated via ETB receptors. This inhibitory effect may in part involve protein kinase C activation.
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PMID:Endothelins inhibit cyclic-AMP induced renin gene expression in cultured mouse juxtaglomerular cells. 880 79

1. A pharmacological characterization was made of the effects of lysophosphatidyl-inositol (lysoPI) and -ethanolamine (lysoPE) on the Ca(2+)-sensitivity of contraction in alpha-toxin permeabilized rat mesenteric arteries. The effect of GTP gamma S (G-protein activator), diacylglycerols (DAGs, dioctanoyl glycerol (diC8) and 1-stearoyl-2-arachidonoyl-sn-glycerol) and phorbol myristate acetate (PMA, protein kinase C (PKC) activator) on Ca(2+)-sensitivity was also assessed. 2. LysoPI increased the Ca(2+)-sensitivity, demonstrated by both an increase in tension induced by 1 microM [Ca2+]free and an increase in the Ca(2+)-sensitivity of Ca2+ concentration-tension curves. LysoPE did not enhance force or Ca(2+)-sensitivity. 3. GTP gamma S enhanced force at constant Ca2+, increased the Ca(2+)-sensitivity, and increased force under Ca(2+)-free conditions. PMA also increased force at constant Ca2+ and increased Ca(2+)-sensitivity, but caused no force development under Ca(2+)-free conditions. 4. DAGs, both diC8 and the more physiological relevant DAG, 1-stearoyl-2-arachidonoyl-sn-glycerol, enhanced force at constant Ca2+ and increased the Ca(2+)-sensitivity. DiC8, in contrast to 1-stearoyl-2-arachidonoyl-sn-glycerol, caused force development under Ca(2+)-free conditions and substantially enhanced force at maximal Ca(2+)-induced contraction. GDP-beta-S abolished the increased Ca(2+)-sensitization induced by noradrenaline, but not that by DAGs. 5. The PKC inhibitor calphostin C completely abolished Ca(2+)-sensitization induced by all of the Ca(2+)-sensitizing agents. 6. These results show that lysoPI can increase the Ca(2+)-sensitivity of smooth muscle contraction, and the Ca(2+)-sensitization induced by DAGs was not completely G-protein mediated, because it was not inhibited by GDP-beta-S. A central role for PKC in regulation of Ca(2+)-sensitization in rat mesenteric small arteries was indicated by the abolishment of Ca(2+)-sensitization by calphostin C.
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PMID:Calphostin C-sensitive enhancements of force by lysophosphatidylinositol and diacylglycerols in mesenteric arteries from the rat. 887 51


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