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)

Thromboxane (Tx)A2 has been reported to play an important role in modulating airway contractility under various conditions associated with airways inflammation. To identify its potential role in contributing to airway smooth muscle (ASM) hyperplasia, a characteristic feature of asthmatic airways, the mitogenic effect and mechanism of action of TxA2 were investigated in cultured rabbit ASM cells. The stable TxA2 mimetics, carbocyclic TxA2 (CTA2) and U-46619, elicited dose-dependent (10(-12) to 10(-6) M) increases in ASM cell number and induced acute augmentation of intracellular inositol 1,4,5-trisphosphate accumulation. The latter action was blocked by neomycin, a phospholipase C inhibitor; however, neomycin had no effect on the promitogenic action of the TxA2 mimetics. In contrast, TxA2-induced ASM cell proliferation was inhibited by inhibitors of phospholipase A2 and 5-lipoxygenase, as well as blockade of the leukotriene (LT)D4 receptor. Moreover, in complementary studies, we found that exogenous administration of LTD4 (10(-14) to 10(-6) M) potently induced ASM cell proliferation and that the TxA2 mimetics evoked the enhanced release of endogenous leukotrienes from the cultured ASM cells. Taken together, these observations provide new evidence that 1) TxA2 stimulates ASM cell proliferation; 2) the promitogenic effect of TxA2 is associated with activation of phospholipase A2; and 3) the latter mediates ASM cell proliferation via the release and autocrine mitogenic action of leukotrienes. The findings support a potential role for TxA2 in contributing to the characteristic increase in ASM cell mass obtained in asthma and other chronic airway diseases.
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PMID:Role and mechanism of thromboxane-induced proliferation of cultured airway smooth muscle cells. 144 59

Phospholipids accumulate within the lysosomes of various cells from individuals taking amiodarone. Studies on cultured cells suggest that inhibition of lysosomal phospholipase A1 and phospholipase A2 by amiodarone may be responsible for this derangement in phospholipid metabolism. Inhibition of lysosomal phospholipases by amiodarone has been suggested as a mechanism of its toxicity, but this relationship has not been clearly established. To examine this question, membrane phospholipids of cultured bovine pulmonary artery endothelial cells (BPAEC) were labeled with 14C-stearic acid, 3H-arachidonic acid, 14C-choline, or 14C-ethanolamine. Radiolabeled BPAEC were then exposed to various concentrations of amiodarone, and endothelial phospholipase activity was measured by isolating and quantifying various phospholipase products. These findings were compared to a standard indicator of endothelial cytotoxicity using 51Cr release. Six-hour exposures to 5 to 20 micrograms/ml amiodarone produced no BPAEC toxicity and were accompanied by some evidence of decreased phospholipid hydrolysis. At concentrations above 20 micrograms/ml, amiodarone caused significant BPAEC toxicity as indicated by 51Cr release, and this was closely associated with the liberation of substantial amounts of 3H-arachidonic acid and 14C-stearic acid from phosphatidylcholine and phosphatidylethanolamine. In BPAEC labeled with 14C-choline and 14C-ethanolamine, cytotoxic doses of amiodarone caused accumulations of 14C-phosphocholine and phosphorylethanolamine, expected products of phospholipase C, but without increases in phospholipase A products. We conclude that exposure of BPAEC to toxic concentrations of amiodarone is associated with extensive hydrolysis of phosphatidylcholine and lysophosphatidylethanolamine via a phospholipase C-specific mechanism, and suggest that this may be a mechanism in the pathogenesis of amiodarone toxicity.
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PMID:Amiodarone-induced endothelial injury is associated with phospholipase C-mediated hydrolysis of membrane phospholipids. 145 16

We describe here and partially characterize a Ca(2+)-independent phospholipase A2 that acts on phosphatidylinositol in normal human peripheral blood neutrophils. Neutrophils incubated with myo-[3H]inositol to form [3H]phosphatidylinositol and then stimulated with the calcium ionophore A23187 produced [3H]lysophosphatidylinositol. This deacylation was further characterized in cell sonicates by the specific release of [3H]arachidonic acid from exogenous [1-14C]stearoyl-2-[3H]arachidonyl-phosphatidylinositol. This phospholipase A2 is Ca2+ independent, retaining full activity in the presence of 10 mM EDTA, and is optimally active at alkaline pH (pH 9). A phosphatidylinositol-hydrolyzing phospholipase C activity was characterized by the production of [3H]-/[14C]-diglycerides. This phospholipase C activity is dependent on the presence of exogenous Ca2+ and is optimally active at neutral pH (pH 7.5). The lipoxygenase/cyclooxygenase inhibitors eicosatetraenoic acid and nordihydroguaiaretic acid and the calmodulin antagonist trifluoperazine were the only compounds tested that showed significant inhibition of phospholipase A2 activity. However, none of these phosphatidylinositol-hydrolyzing phospholipase A2 inhibitory compounds resulted in the accumulation of any radiolabeled diglyceride, monoglyceride, or phosphatidic acid intermediates. Following subcellular fractionation on sucrose density gradients, it was found that the plasma membrane-enriched fractions contained the highest specific activity for phospholipase A2; however, the cytosolic fraction contained a large part of the total phospholipase A2 activity. Furthermore, when neutrophils were first exposed to several agents, including lipopolysaccharide, phorbol myristate acetate, or N-formyl-methionyl-leucyl- phenylalanine, and then subfractionated, there was a significant translocation of the enzyme activity from the cytosolic fraction to the membrane-enriched fractions. These data suggest that this Ca(2+)-independent, phosphatidylinositol-hydrolyzing phospholipase A2 may play an important role in early cell activation, providing free arachidonic acid for subsequent metabolism into biologically active eicosanoids.
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PMID:Phosphatidylinositol hydrolysis by phospholipase A2 and C activities in human peripheral blood neutrophils. 146 38

The activation of heterotrimeric G proteins results in the exchange of GDP bound to the alpha-subunit for GTP and the subsequent dissociation of a complex of the beta- and gamma-subunits (G beta gamma). The alpha-subunits of different G proteins interact with a variety of effectors, but less is known about the function of the free G beta gamma complex. G beta gamma has been implicated in the activation of a cardiac potassium channel, a retinal phospholipase A2 (ref. 9) and a specific receptor kinase, and in vitro reconstitution experiments indicate that the G beta gamma complex can act with G alpha subunit to modulate the activity of different isoforms of adenylyl cyclase. Of two phospholipase activities that can be separated in extracts of HL-60 cells, purified G beta gamma is found to activate one of them. Here we report that in co-transfection assays G beta gamma subunits specifically activate the beta 2 and not the beta 1 isoform of phospholipase, which acts on phosphatidylinositol. We use transfection assays to show also that receptor-mediated release of G beta gamma from G proteins that are sensitive to pertussis toxin can result in activation of the phospholipase. This effect may be the basis of the pertussis-toxin-sensitive phospholipase C activation seen in some cell systems (reviewed in refs 13 and 14).
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PMID:Subunits beta gamma of heterotrimeric G protein activate beta 2 isoform of phospholipase C. 146 34

Human endometrium contains specific binding sites for iodinated endothelin (ET)-1, ET-2 and ET-3, and ET-1 stimulates prostaglandin (PG) F2 alpha synthesis from explants of proliferative endometrium in short-term culture. This study has investigated the cellular responses of normal proliferative endometrium to ET-1. Radioimmunoassay was used to measure PG release and Dowex anion-exchange column chromatography was utilized to assess the accumulation of inositol phosphates. Endothelin-1 induced a significant increase in PGF2 alpha release (basal median: 1465 pg/mg per 60 min (range: 541-3935 pg/mg per 60 min); ET-1-stimulated: 1813 pg/mg per 60 min (1021-5714 pg/mg per 60 min); P < 0.04 using Wilcoxon signed rank test). The effect of ET-1 was attenuated in the presence of the phospholipase A2 inhibitor quinacrine. Endothelin-1 induced a rapid, transient and concentration-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), measured by the accumulation of tritiated inositol phosphates. Following a 1-min stimulation with ET-1 (100 nmol/l), [3H]inositol mono-, bis- and trisphosphate fractions increased from median values of 490.0 d.p.m./mg dry wt (range: 348.0-807.0 d.p.m./mg dry wt), 120.0 d.p.m./mg dry wt (93.6-144.1 d.p.m./mg dry wt) and 67.0 d.p.m./mg dry wt (54.2-85.0 d.p.m./mg dry wt) to 939.0 d.p.m./mg dry wt (635.9-1596.0 d.p.m./mg dry wt; P < 0.03), 145.0 d.p.m./mg dry wt (127.0-293.9 d.p.m./mg dry wt; P < 0.05) and 146.0 d.p.m./mg dry wt (77.5-187.0 d.p.m./mg dry wt; P < 0.03) respectively. These results suggest that ET-1 activates the phospholipase A2 and PtdIns(4,5)P2-specific phospholipase C in human proliferative endometrium, resulting in the generation of PGF2 alpha and second messengers respectively which are pivotal to endometrial function.
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PMID:Activation of phospholipase A2 and phospholipase C by endothelin-1 in human endometrium. 147 44

The stimulation of phospholipase D (PLD) activity by endothelin-1 (ET1) was investigated in rabbit iris sphincter prelabelled with [3H]myristic acid. In the presence of 0.5% ethanol, ET1 caused a time- and dose-dependent increase in the production of [3H]phosphatidylethanol ([3H]PEt). Within 30 s the peptide increased PEt formation by 30% and after 5 min increased it by 140%. The EC50 value for ET1-stimulated PEt formation was found to be 30 nM. This value is appreciably lower than the EC50 we previously obtained for ET1-induced inositol trisphosphate production (45 nM), but considerably higher than that for arachidonic acid release (1 nM). PEt formation was significantly stimulated by prostaglandin F20, phorbol 12,13-dibutyrate (PDBu), chloroform, A23187 and A1F4-, but it was not affected by carbachol or the platelet-activating factor. PDBu-stimulated PEt formation was blocked by staurosporine and it was not potentiated by A23187. Staurosporine had no effect on ET1-stimulated PEt formation. Our data indicate that ET1 stimulation of PLD occurs independently of protein kinase C activation, phospholipase C activation and intracellular Ca2+ mobilization, and phospholipase A2 activation. In this tissue the ET1 receptor is probably coupled to the three phospholipases through several G-proteins, and this appears to be species and receptor type specific.
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PMID:Activation of phospholipase D by endothelin-1 and other pharmacological agents in rabbit iris sphincter smooth muscle. 148 66

There is evidence suggesting that fluid shear stress activates phospholipid turnover in endothelial cells, but it is not clear which phospholipids are involved in the transduction of the flow signal. Cultured human umbilical-vein endothelial cells were prelabeled with [14C]-arachidonic acid and subjected to laminar shear stresses of 0.4, 1.4 and 22 dyn/cm2 for times up to 30 min, after which the distribution of the radioactivity in the phospholipids was determined. We observed decreases in labeled phosphatidylinositol, phosphatidylethanolamine and phosphatidic acid at 10-30 s, and increases in labeled diacylglycerol (DG) and free arachidonate, as well as a simultaneous elevation in inositol 1,4,5-triphosphate (IP3) levels. A second peak in IP3 levels was observed 10 min after the onset of shear. This is in contrast with agonist-stimulated endothelial cells, where IP3 levels go back to initial values within a few minutes after stimulation. The flow-induced IP3 response was the same in the presence or absence of ATP and serum in the perfusing medium. These results are consistent with the activation of phospholipase C, phospholipase A2 and DG lipase by shear stress. This suggests that several phospholipids are involved in the production of free arachidonic acid and DG, which are likely to be important mediators of the shear stress signal. In addition, flow may lead to a chronic stimulation of endothelial-cell metabolism.
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PMID:Fluid shear stress stimulates membrane phospholipid metabolism in cultured human endothelial cells. 148 90

In the kidney, adenosine plays important regulatory roles, including renal blood flow, glomerular filtration rate, renin secretion, tubuloglomerular feedback, tubular reabsorption of sodium and water, sympathetic neurotransmitter release, and erythropoietin secretion. These functions are mediated through adenosine 1 (A1)-receptors and adenosine 2 (A2)-receptors. These receptors couple to the inhibition and stimulation of adenylate cyclase, through Gi and Gs proteins, respectively. A variety of other effecter systems have been reported to be coupled to A1 receptors, including phospholipase C, phospholipase A2 and potassium, as well as Ca++ channels. Recently, A1 receptors, A2 receptors and novel A2 receptor have been cloned, sequenced and expressed. In association with the development of selective adenosine analogues, we are now ready to take up problems at the biochemical and molecular biological levels.
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PMID:[Adenosine and adenosine receptors in the kidney]. 149 49

Interleukin-1 (IL-1) can initiate the synthesis of prostaglandins which in turn act as endogenous modulators of IL-1 production. The human monocyte/macrophage synthesizes various eicosanoids through the activation of the cellular phospholipase system. Cell stimulation results in the activation of phospholipase A2 (PLA2) whose major substrate is phosphatidylcholine (PC) and the release of the eicosanoid precursor arachidonic acid (AA) from PC. Another pathway is the stimulation of a phospholipase C (PLC) mainly active on phosphoinositides and the resulting formation of inositol phosphates (IPs) and diacylglycerol (DAG). Phospholipids other than phosphoinositides can also be hydrolysed by PLC to give rise to DAG. Studies have shown that IL-1 does not activate the IP pathway, but it primarily stimulates a PLC linked to phosphatidylethanolamine in cultured rat mesangial cells, and a PLC linked to PC in Jurkart cells. We have stimulated human monocytes with IL-1 and calcium ionophore A23187 and we have observed their effect on the phospholipase system. The results indicate that IL-1 does not activate the formation of IPs in cells labeled with [3H]myo-inositol. In contrast, in cells labeled with [3H]AA, IL-1 causes the formation of DAG associated with the hydrolysis of PC. Moreover, after stimulation with IL-1 there is no accumulation of free AA which would indicate that there has been no activation of PLA2, which occurs instead with A23187 stimulation. These data suggest that, in monocytes, IL-1 does not directly stimulate a PLA2 or a PLC active on phosphatidylinositol; instead it primarily stimulates a PLC active on PC.
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PMID:In human monocytes interleukin-1 stimulates a phospholipase C active on phosphatidylcholine and inactive on phosphatidylinositol. 151 Jul 17

1. Independent of its effects on renal haemodynamics and glomerular filtration, angiotensin II (AII) has direct actions on the proximal tubule involving transepithelial Na+, H+, HCO3-, and water reabsorption, ammoniagenesis, gluconeogenesis and renal growth. 2. The effects of AII on water and electrolyte transport are biphasic and dose-dependent, such that low concentrations (10(-12)-10(-9) mol/L) stimulate reabsorption whereas high concentrations (10(-7)-10(-6) mol/L) inhibit reabsorption. Similar dose-response relations have been obtained for luminal and peritubular addition of AII. 3. The cellular responses to AII are mediated via an AT-1 receptor coupled via G-regulatory proteins to several parallel signal transduction pathways. Low doses inhibit the basolateral adenylate cyclase, lower intracellular cAMP and withdraw the inhibitory effect of protein kinase A on the luminal Na/H exchanger. Stimulation of this exchanger may also occur due to AII-receptor activation of phospholipase C to release diacyl glycerol, or by local transduction in the brush-border membrane involving phospholipase A2. 4. Inhibition of proximal fluid reabsorption is associated with increased intracellular Ca2+ released from intracellular stores, or entering via voltage-sensitive channels in response to the release of inositol-1,4,5-trisphosphate, or following Ca2+ channel opening induced by the arachidonic acid metabolite 5,6-epoxy-eicosatrienoic acid. 5. The stimulatory actions of peritubular AII on proximal transport are inhibited by physiological concentrations of atrial natriuretic factor (ANF) and by parathyroid hormone (PTH). 6. It is concluded that intrarenal AII acts to maintain optimal matching of fluid reabsorption and filtered load in response to changes in sodium balance, as well as to promote acidification of the urine during acidosis and perhaps to potentiate tubular growth following renal injury.
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PMID:Regulation of proximal tubule function by angiotensin. 151 68


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