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 goal of the present study was to identify the molecular mechanism underlying desensitization of endothelin-1 receptor-mediated phosphoinositide response in cultured neonatal rat heart cells. Endothelin elicited a concentration-dependent (EC50 = 2.2 x 10(-9) M) increase of inositol-phosphate production with a much higher potency than phenylephrine (EC50 = 1.4 x 10(-6) M). Endothelin-1 (10(-8) M) evoked phosphoinositide turnover in the presence of 10 mM LiCl, which was greatly attenuated after 30-45 min of continuous stimulation with agonist, apparently resulting in a total absence of further inositol-phosphate accumulation. However, when the uncompetitive inositol monophosphatase inhibitor Li+ was only present during the last 30 min of 150 min incubation, the inositol-phosphate accumulation was decreased to a steady state of 33% of the initial rate. The loss of responsiveness of cardiomyocytes to endothelin-1 was not brought about by a limiting supply of phospholipase C substrate phosphatidylinositol 4,5-bisphosphate. A very rapid resynthesis of this substrate took place as its level remained almost constant during 45 min stimulation with 10(-8) M endothelin-1 while the accumulation of inositol-phosphates was at least 15-fold higher than the initial cellular phosphatidylinositol 4,5-bisphosphate content. After 120 min preincubation of cells with 10(-9) M endothelin-1 the activation of phospholipase C by a second higher dose (10(-8) M) was severely (67%) inhibited at the same time leaving the induction of phosphoinositide turnover by phenylephrine (10(-4) M) virtually intact. Preincubation with phenylephrine (3 x 10(-6) M) also led to inhibition of the phenylephrine (10(-4) M)-mediated inositol-phosphate response (36% inhibition) while the endothelin-1 (10(-8) M) response was not affected. Addition of a direct activator of protein kinase C, phorbol 12-myristate 13-acetate, led to inhibition of the endothelin-1 evoked phosphoinositide turnover but the rate of desensitization was not affected. Inhibition of protein kinase C with staurosporine did not alter the time course of desensitization. In conclusion, the activity of the phosphoinositide cycle in cardiomyocytes is homologously desensitized after stimulation with endothelin-1. The desensitization is not likely to be due to either depletion of phospholipase C substrate or to the activation of protein kinase C by inositol 1,4,5-trisphosphate-mobilized Ca2+ and elevated 1,2-diacylglycerol levels.
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PMID:Homologous desensitization of the endothelin-1 receptor mediated phosphoinositide response in cultured neonatal rat cardiomyocytes. 838 49

The aim is to summarize briefly the evidence for the existence and possible functions of receptor-mediated activity of phospholipases C and D in the myocardium. Muscarinic, alpha 1-adrenergic, angiotensin II, endothelin-1, thrombin, adenine nucleotide and opioid peptide receptors are all linked through GTP-binding proteins to phospholipase C which hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) in the myocardium. Events that are not linked to receptors, such as mechanical loading (stretching) of cardiomyocytes, can also activate phospholipase C. The high capacity for resynthesis of PIP2 maintains the pool of PIP2, even during maximal activation of phospholipase C. Activation of phospholipase C by endothelin-1, alpha 1-adrenoceptor and angiotensin II, is subject to different rates of homologous desensitization. Protein kinase C is probably not involved in the desensitization of the response to endothelin-1. One of the products of the hydrolysis of PIP2, inositol 1,4,5-trisphosphate (IP3), releases Ca2+ from the sarcoplasmic reticulum. This intracellular response seems to be causally related to positive inotropy. The phosphorylated product of IP3, inositol 1,3,4,5-tetrakisphosphate (IP4), is believed to play a role in the handling of intracellular Ca2+, as well as in the inotropic response; however, its formation is controversial. At present the oscillations in the level of intracellular Ca2+ underlying, for example, the positive inotropy induced by alpha 1-adrenoceptors or endothelin are not clearly identified. The other product of phospholipase C, 1,2-diacylglycerol, activates Ca(2+)-dependent protein kinase C and potentially controls a wide array of cellular functions such as ion transport, myofibrillar Ca2+ sensitivity, "cross-talk" between phospholipases C and D, gene expression, protein synthesis and hypertrophic cell growth. Alterations in the fatty acid composition, particularly the polyunsaturated fatty acids, modify the phosphoinositide response induced by hormones. Cultured cardiomyocytes, incubated in sera containing the fatty acids 18:2n-6 or 20:5n-3, but not 18:0 and 18:1n-9, show a decrease in the phospholipase C responses mediated by alpha 1-adrenoceptors. The fatty acid composition of myocardial phosphatidyl inositol 4-monophosphate (PIP) and PIP2 differs from that of phosphatidylinositol, which indicates that phosphatidylinositol kinases have a certain substrate specificity or have access to localized phosphatidylinositol molecules. The estimation of the level of stimulated 1,2-diacylglycerol is complicated by the contribution of the activity of receptor-mediated phospholipase D. The identification of the molecular species of 1,2-diacylglycerol is crucial in establishing the roles and the sources of 1,2-diacylglycerol. The fatty acids covalently bound in the membrane phospholipids may also influence phospholipases C and D.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Receptor-mediated signalling pathways acting through hydrolysis of membrane phospholipids in cardiomyocytes. 840 19

The regulation of the inositide signalling pathway and [Ca2+]i by endothelin (ET) peptides was investigated in human glomerular epithelial cells in culture. Endothelin-1 and -2 induced an accumulation of inositol phosphates in a time- and dose-dependent manner. The baseline of [Ca2+]i in glomerular epithelial cells was 109 +/- 2.8 nmol/l, n = 60. Endothelin-1 (ED50: approx. 3 x 10(-9) mol/l) caused a rapid and transient rise in [Ca2+]i as detected by fura-2 microfluorimetry studies. The endothelin-1-induced inositol phosphate accumulation was inhibited by the selective ETA receptor antagonist BQ123. Endothelin-3 and BQ3020, a selective ETB receptor agonist, showed no effect. The results suggest an ETA-mediated pathway. This study demonstrates an ETA-mediated transmembrane signalling via phospholipase C with consecutive elevation of inositol phosphates and intracellular calcium. Since endothelin peptides contribute to both normal renal function and renal dysfunction, this study adds further knowledge on glomerular cell regulation.
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PMID:Regulation of phosphoinositide hydrolysis and cytosolic free calcium induced by endothelin in human glomerular epithelial cells. 853 18

C6 glioma cells possess endothelin ETA receptor and P2 purinoceptor coupled to two signaling pathways, i.e. phosphoinositide turnover and inhibition of adenylyl cyclase. In this study, the effects of raising cyclic AMP levels on the inositol phospholipid hydrolysis and adenylyl cyclase inhibition caused by endothelin-1 and ATP in C6 glioma cells were examined. Pretreatment with cAMP generating agents (forskolin, isoproterenol and cholera toxin) or dibutyryl cAMP for 10 min-3 h did not affect the inositol phosphate accumulation caused by endothelin and ATP. Long-term (8-24 h) pretreatment with isoproterenol, forskolin, cholera toxin or dibutyryl cAMP resulted in a 40-50% inhibition of endothelin- and ATP-stimulated inositol phosphate accumulation, whereas the EC50 values of endothelin and ATP were not affected. Consistent with the effects on endothelin and ATP, NaF-induced inositol phosphate formation was also inhibited by cAMP generating agents to a similar extent. Permeabilized cells from 24 h isoproterenol-or forskolin-pretreated C6 cells also showed a diminished Ca(2+)-sensitivity of phosphoinositide-specific phospholipase C and also attenuated the potentiation response caused by GTP gamma S. The inhibitory effects on adenylyl cyclase by endothelin, ATP and 2-methylthio-ATP were unaffected by 24 h pretreatment with isoproterenol or forskolin. Long-term treatment with dibutyryl cGMP did not affect the two signaling pathways caused by ATP and endothelin. It is concluded that the phosphoinositide turnover, but not the adenylyl cyclase inhibition caused by endothelin and ATP in C6 cells, was inhibited by protein kinase A-dependent pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of protein kinase A activation on endothelin- and ATP-induced signal transduction. 854 42

The increased expression of immunoreactive endothelin-1 (ET-1) in reactive astrocytes and its mitogenic effects on astrocytes and glioma cell lines, have implicated endothelins in the development of reactive gliosis. In this study, an increase in DNA synthesis in rat type I astrocytes was observed after cultures were transiently exposed to ET-1 for 15 min, suggesting that early signal transduction events are essential and sufficient for the propagation of the ET-1-induced mitogenic signal. Prompt increases in inositol triphosphate (IP3) formation and [Ca2+]i were observed upon the addition of ET-1 to these cells. The ET-1-evoked increase in [Ca2+]i consisted of an initial peak which was preserved in Ca(2+)-free medium, and a sustained phase which was abolished in Ca(2+)-free medium and partly attenuated by nifedipine. ET-1 also increased the activity of membrane-associated protein kinase C (PKC) and induced the in vivo phosphorylation of the 85 kD MARCKS protein, an endogenous PKC-specific substrate. The ET-1-evoked increases in DNA synthesis, IP3, [Ca2+]i, membrane PKC, and 85 kD MARCKS protein phosphorylation in rat cortical astrocytes were prevented by either the selective endothelin ETA receptor antagonist, BQ-123, or the phospholipase C (PLC)-specific inhibitor, U-73122. However, the inhibition of PKC activity did not affect ET-1-induced DNA synthesis in rat cortical astrocytes. These results suggest that ET-1-induced IP3 and/or [CA2+]i responses, but not the activation of PKC, are essential for the growth-factor like actions of ET-1 in rat cortical astrocytes.
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PMID:The role of intracellular calcium and protein kinase C in endothelin-stimulated proliferation of rat type I astrocytes. 856 63

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

The three cloned alpha1-adrenergic receptor (AR) subtypes, alpha1B, alpha1C, and alpha1D, can all couple to the same effector, phospholipase C, and the reason(s) for conservation of multiple subtypes remain uncertain. All three alpha1-ARs are expressed natively in cultured neonatal rat cardiac myocytes, where chronic exposure to the agonist catecholamine norepinephrine (NE) induces hypertrophic growth and gene transcription. We show here, using RNase protection, that the alpha1-AR subtype mRNAs respond in distinctly different ways during prolonged NE exposure (12 72 h). Alpha1B and alpha1D mRNA levels were repressed by NE, whereas alpha1C mRNA was induced. Changes in mRNA levels were mediated by an alpha1-AR, were not explained by altered mRNA stability, and were reflected in receptor proteins by [3H]prazosin binding. alpha1-AR-stimulated phosphoinositide hydrolysis and myocyte growth were not desensitized. Three other hypertrophic agonists in culture, endothelin-1, PGF2alpha, and phorbol 12-myristate 13-acetate, also induced alpha1C mRNA and repressed alpha1B mRNA. In myocytes from hearts with pressure overload hypertrophy, alpha1 mRNA changes were identical to those produced by NE in culture. These results provide the first example of a difference in regulation among alpha1-AR subtypes expressed natively in the same cell. Transcriptional induction of the alpha1C-AR could be a mechanism for sustained growth signaling through this receptor and is a common feature of a hypertrophic phenotype in cardiac myocytes.
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PMID:Alpha1-adrenergic receptor subtype mRNAs are differentially regulated by alpha1-adrenergic and other hypertrophic stimuli in cardiac myocytes in culture and in vivo. Repression of alpha1B and alpha1D but induction of alpha1C. 862 54

In the current study, endothelin-1 (ET-1) worked as a mitogen on Chinese hamster ovary cells stably expressing human endothelinA; when applied to serum-deprived cells, ET-1 caused dose-dependent increase in [3H]thymidine incorporation and cell proliferation. No synergism was observed between the effect of ET-1 and that of insulin-like growth factor-1/basic fibroblast growth factor. Both the inhibition of intracellular Ca2+ response by phospholipase C inhibitor U73122 and the down-regulation of protein kinase C (PKC) by pretreatment with phorbol 12-myristate-13-acetate (PMA) partially blocked the ET-1-induced mitogenic responses. Wortmannin, a phosphatidylinositol-3-kinase inhibitor, caused dose-dependent inhibition of the ET-1-induced mitogenic responses in both PMA-treated and -untreated cells. Wortmannin also inhibited ET-1-induced increase in phosphatidylinositol trisphosphate formation and activation of mitogen-activated protein kinase (MAPK), whereas it failed to inhibit PMA-induced activation of MAPK. In accordance with its effect on MAPK activation, wortmannin inhibited ET-1-induced activation of Raf-B, whereas it failed to inhibit the effect of PMA. These results suggested the role of a Ca2+/PKC-independent, wortmannin-sensitive signaling pathway that linked ETA and MAPK cascade in the mitogenic signaling activated by ETA.
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PMID:Endothelin-1-induced mitogenic responses of Chinese hamster ovary cells expressing human endothelinA: the role of a wortmannin-sensitive signaling pathway. 864 84

Small GTP-binding proteins of the Rho family are implicated in the in vitro regulation of phosphatidylcholine hydrolysis by phospholipase D (PLD). However, their role in agonist-stimulated PLD activity in whole cells is not clear. The ribosyltransferase C3 from Clostridium botulinum modifies Rho proteins and inhibits their function. When introduced into rat1 fibroblasts by scrape-loading, C3 inhibited PLD activity stimulated by lysophosphatidic acid (LPA), endothelin-1, or phorbol ester. Neither the time course nor agonist dose response for LPA-stimulated PLD activity was altered in C3-treated cells. In contrast to the effects of C3 on PLD activity, agonist-stimulated phosphatidylinositol-phospholipase C activity was not altered in C3-treated cells. Surprisingly, C3 treatment led to a decrease in the amount of RhoA protein, indicating that the loss of PLD activity in response to agonist was partly due to the loss of Rho proteins. As described previously, C3 treatment led to the inhibition of LPA-stimulated actin filament formation. However, disruption of actin filaments with cytochalasin D caused only a minor inhibition of LPA-stimulated PLD activity. Interestingly, stimulation of cells with LPA caused a rapid enrichment of RhoA in the particulate fraction of cell lysates. These data support an in vivo role for RhoA in agonist-stimulated PLD activity that is separate from its role in actin fiber formation.
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PMID:Evidence for Rho-mediated agonist stimulation of phospholipase D in rat1 fibroblasts. Effects of Clostridium botulinum C3 exoenzyme. 866 44


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