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)

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

Using a perfused rat hindleg system, release of tissue-type plasminogen activator (t-PA) from endothelial cells could be induced by platelet-activating factor (PAF), bradykinin, substance P, thrombin, carbachol and A23187, while this release was inhibited by mepacrine and by nor-dihydroguaiaretic acid. The PAF-induced release of t-PA was inhibited by the cytochrome P-450 mono-oxygenase inhibitors, metyrapone, ketoconazole and SKF 525A and by eicosatetraynoic acid but not by indomethacin or BW 755C, suggesting the involvement of epoxygenase products. The PAF-induced release of von Willebrand factor (vWF) was also similarly inhibited by the cytochrome P-450 monooxygenase inhibitor, ketoconazole. Phorbol ester and phospholipase C induced the release of both t-PA and vWF, while phospholipase A2 did not. The release induced by PAF and bradykinin was not influenced by pretreatment with pertussis toxin.
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PMID:The involvement of products of the phospholipase pathway in the acute release of tissue-type plasminogen activator from perfused rat hindlegs. 152 62

The levels of brain free fatty acids rapidly increase after the onset of ischemia. The purpose of this study was to investigate the action of phospholipases A2 and C during complete ischemia based on the effects of a phospholipase C inhibitor (phenylmethylsulfonyl fluoride) and the N-methyl-D-aspartate antagonist MK-801 on the release of free fatty acids in rat neocortex. Complete brain ischemia was induced in rats with cardiac arrest by intracardiac injection of KCl. Free fatty acid levels in the neocortex were measured 0, 2, 4, and 8 minutes after cardiac arrest. Phenylmethylsulfonyl fluoride inhibited the release of free fatty acids primarily from phosphatidylinositol during the first 2 minutes of ischemia and from phosphatidylcholine and phosphatidylethanolamine at 4 to 8 minutes of ischemia. Conversely, MK-801 inhibited free fatty acid release mainly from phosphatidylcholine and phosphatidylethanolamine at 2 to 4 minutes of ischemia. These results indicate that the release of free fatty acids during the first 2 minutes of ischemia can be attributed mostly to the action of phospholipase C, and that the activation of phospholipase C further influences the activation of phospholipase A2 in the subsequent course, while phospholipase A2 predominantly acts after 2 minutes of ischemia.
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PMID:Action of phospholipases A2 and C on free fatty acid release during complete ischemia in rat neocortex. Effect of phospholipase C inhibitor and N-methyl-D-aspartate antagonist. 153 28

The present study specifically addresses the role of protein kinase C (PKC) activation in human endothelial cell Ca2+ mobilization, a response that is functionally coupled to the production of the potent arachidonate (AA) metabolite, prostacyclin (PGI2). Phorbol 12-myristate 13-acetate (PMA), alpha-thrombin, and sodium fluoride (NaF), a direct G-protein activator, produced a rapid and time-dependent translocation of PKC from the cytosol to the membrane. Activation of PKC by brief pretreatment of human umbilical vein endothelial cell (HUVEC) monolayers with PMA resulted in the inhibition of NaF-induced inositol phosphate increases and attenuation of both alpha-thrombin- and NaF-activated increases in intracellular Ca2+ (Ca2+i). Ca2+ mobilization induced by ionophore A23187 was not affected by PKC preactivation, suggesting PKC-dependent negative feedback inhibition of phosphatidylinositol (PI)-specific phospholipase C (PLC). Agonist-stimulated AA release and PGI2 synthesis in PMA-pretreated cultured human endothelial cells, however, was potentiated, and the enhanced PGI2 synthesis produced by A23187, NaF, and alpha-thrombin was dependent upon the dose of PMA. Treatment of HUVEC monolayers with an intracellular Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid-acetoxymethylester (BAPTA-AM), dramatically reduced alpha-thrombin-, NaF-, and A23187-induced PGI2 synthesis, demonstrating the importance of Ca2+i availability in PGI2 synthesis. BAPTA pretreatment did not inhibit PMA-induced PKC activation, and BAPTA-mediated inhibition of agonist-stimulated PGI2 synthesis was partially attenuated by prior PMA pretreatment. Staurosporine, a potent PKC inhibitor, at concentrations that inhibited PKC-induced phosphorylation of histone-1, augmented both alpha-thrombin- and NaF-induced production of inositol phosphates but markedly inhibited alpha-thrombin-, NaF-, and A23187-induced PGI2 synthesis. The downregulation of PKC activity by prolonged PMA treatment (18 h) produced similar inhibition of PGI2 synthesis by these agonists (approximately 50% inhibition). These studies indicate that the integrated phospholipase A2 and PLC activities are under complex regulation by factors that include both PKC activation and [Ca2+i]. PKC exerts dual effects on prostaglandin synthesis via negative regulation of Gp-coupled PI-specific PLC and positive feedback regulation of AA release and PGI2 synthesis. PKC is thus a critical determinant in the regulation of human endothelial cell prostaglandin synthesis by both receptor-mediated and G-protein-dependent cellular activation.
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PMID:Role of protein kinase C in the regulation of prostaglandin synthesis in human endothelium. 154 Mar 95

In neonatal cultured cardiac myocytes under normoxic conditions, 32Pi incorporation pattern into various phospholipids, and double-labeling experiments with 32Pi and [3H]methyl choline, suggest that phosphatidylcholine and phosphatidylinositol are turned over rapidly, whereas the turnover of phosphatidylethanolamine is probably much slower. While increased levels of the corresponding lysophospholipids were not found under anoxia, release of diacylglycerol and phosphorylcholine was observed. These data strongly suggest that phospholipase C, and not phospholipase A2, is involved in phospholipid degradation in cultured cardiomyocytes under anoxic conditions.
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PMID:Anoxic injury accelerates phosphatidylcholine degradation in cultured cardiac myocytes by phospholipase C. 154 65

We have investigated the effect of cis-diamminedichloroplatinum(II) (CDDP) on signal transduction pathways. CDDP treatment did not cause any change in the binding of [3H]-phorbol dibutyrate to PC-9 (human lung adenocarcinoma cell line) cells, a measure of protein kinase C activation. However, 2-h CDDP treatment (20 micrograms/ml) caused approximately 200% increase in 1,2-sn-diacylglycerol (DAG) production and approximately 50% decrease in inositol 1,4,5-triphosphate production. To explore the different source of DAG, we analyzed phospholipids labeled with [14C]choline by TLC and revealed that [14C]choline-labeled phosphatidylcholine (PC) was decreased to 50% by CDDP treatment. This suggested that PC turnover was increased by CDDP-treatment. PC-specific phospholipase C (PC-PLC) activity was increased to 2.5-fold (2.58 +/- 0.28 nmol/mg protein per min) by 2 h CDDP (20 micrograms/ml) treatment compared with control (1.05 +/- 0.24 nmol/mg protein per min). Treatment of CDDP also stimulated PC-PLC in the crude membrane extract from PC-9 cells. CDDP had no effect on the activities of phospholipase A2 and D. Trans-DDP, which has far less cytotoxicity than its stereoisomer, CDDP, did not cause any change in PC-PLC activity. A significant inhibition of DNA synthesis (less than 80%) occurred 4 h after 2 h CDDP (20 micrograms/ml) treatment. These results demonstrated that CDDP-induced PC-PLC activation was an early event in CDDP-induced cytotoxicity and suggested that the effects of CDDP on signal transduction pathways had an important role in CDDP-induced cytotoxicity.
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PMID:Phospholipase C-mediated hydrolysis of phosphatidylcholine is activated by cis-diamminedichloroplatinum(II). 156 1

The immediate reaction products of PLA2-mediated hydrolysis of phospholipids were tested for their ability to induce Ca2+ mobilization from internal stores in permeabilized ob/ob mouse pancreatic islets. Lysophospholipids and unsaturated fatty acids increased the free Ca2+ concentration in the incubation medium of permeabilized ob/ob mouse pancreatic islets. The potency of the lysophospholipids decreased in the following order: lysophosphatidylcholine = lysophosphatidylglycerol much greater than lysophosphatidylinositol greater than lysophosphatidylserine much greater than lysophosphatidylethanolamine. Arachidonic acid and palmitoleic acid had a potency comparable to lysophosphatidylinositol, while palmitic acid was ineffective. The Ca(2+)-mobilizing effect of inositol-1,4,5-trisphosphate (IP3) in permeabilized islet cells was additive to the lysophospholipid effect, indicating different sites of action. Both Ca(2+)-mobilizing effects were counteracted by the polyamine spermine, while the presence of Mg2+ shifted the Ca2+ concentrations to higher levels. Since not only an activation of a phospholipase C but also an activation of a phospholipase A2 with subsequent generation of lysophospholipids and free fatty acids is reported to occur in glucose-induced insulin secretion, the interaction of the phospholipase C reaction product IP3 with a lysophospholipid or an unsaturated fatty acid may affect the extent and duration of the rise in the free cytoplasmic Ca2+ concentration responsible for initiation of insulin secretion.
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PMID:Effect of lysophospholipids, arachidonic acid and other fatty acids on regulation of Ca2+ transport in permeabilized pancreatic islets. 158 37

Phospholipid metabolism is altered during ischemia and post-ischemic reperfusion. Past studies demonstrating elevated myocardial free fatty acid and lysophospholipid content infer accelerated phospholipid degradation involving phospholipase A activity. Recently, ischemic and post-ischemic reperfusion (reperfusion) have been shown to affect levels of phosphoinositide (PPI) degradation products. Considering the role of PPI turnover in regulation of cellular calcium homeostasis, our laboratory and others have suggested that alteration in the metabolism of the inositol phospholipids could play a role in the development of ischemia-induced calcium overload injury. Using an isolated rat heart model (Langendorff perfusion), this study examines the effect of global ischemia and reperfusion on ventricular phosphoinositide-specific phospholipase C (PLC) activity and PLA2 activity. The primary purpose was to determine if ischemia and reperfusion-induced changes in PLC activity could explain previously observed changes in PPI degradation products, and whether PLC and PLA2 activities were similarly or differentially altered by ischemia and reperfusion. PLC and PLA2 activities were measured in cytosolic and total membrane fractions from control (perfused), ischemic (5, 10, 30, and 60 min), and post-ischemic reperfused ventricular tissue. Phospholipase activity was determined under optimal in vitro conditions using exogenous radiolabeled substrates. Alterations in membrane-associated PPI-PLC activity correlated with reported ischemia and reperfusion-induced changes in ventricular content of PPI metabolites. Membrane PLC activity increased slightly at 5 min of ischemia, decreased significantly at 10 min of ischemia, and continued to decrease with longer duration of ischemia (73% of control after 60 min). Cytosolic PPI-PLC activity was decreased at 5 min, and then significantly increased by longer durations of ischemia, while cytosolic PLA2 activity was reduced at all time points. Pretreatment with muscarinic, alpha 1-adrenergic, beta-adrenergic, and adenosine receptor blockers did not alter ischemia-elicited changes in PLC activity. Reperfusion caused a 140% to 200% rise in the activities of all phospholipases in all fractions after 40 min of ischemia, but not after 10 min of ischemia. Results suggest 1) ischemia and reperfusion-elicited alterations in membrane-associated PPI-PLC activity can explain previously observed changes in phosphoinositide turnover metabolites, 2) cytosolic and membrane-associated PPI-PLC and PLA2 activities are not uniformly affected by ischemia, 3) reperfusion following ischemia of sufficient duration initiates uniform activation of PIP2-PLC and PLA2, and 4) because ischemia and reperfusion-induced changes in phospholipase activity can be detected under optimal in vitro assay conditions (removed from the in vivo ischemic microenvironment), it is likely that the enzymes themselves have been altered.
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PMID:Changes in phosphoinositide-specific phospholipase C and phospholipase A2 activity in ischemic and reperfused rat heart. 159 Jul 34


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