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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Addition of phospholipase A2 (PLA2) to isolated proximal tubular segments (PTS) has previously been shown to decrease hypoxic cell death without altering ATP concentrations. The study presented here was undertaken to identify determinant(s) of this protection, and to define the spectrum of injuries against which it can operate. PTS were extracted from mouse kidneys and subjected to diverse forms of injury (hypoxia/reoxygenation, antimycin A, Ca2+ ionophore, amphotericin B, FeSO4, and myohemoglobin). In subtoxic doses, addition of PLA2 significantly reduced hypoxic- and antimycin A-induced injury (percentage of lactate dehydrogenase release); however, a dose-dependent exacerbation of all other forms of injury resulted. The ability of PLA2 to mitigate hypoxic injury remained intact despite the inhibition of Na,K-ATPase (ouabain) or the inducement of cytoskeletal disruption (cytochalasin D). However, it was negated by minimally toxic amphotericin B or Ca2+ ionophore doses, indicating its dependence on preserved ionic gradients. Nevertheless, neither lowering/removing buffer Ca2+ or NaCl concentrations, nor hypertonic mannitol addition reproduced the cytoprotective effect of PLA2. PLA2 induced synergistic deacylation in hypoxic tubules, suggesting that unsaturated fatty-acid accumulation might mediate its cytoprotective effect. The fact that the addition of exogenous arachidonate, but not palmitate, to tubules protected against hypoxia, but worsened nonhypoxic forms of injury, supported this hypothesis. Since arachidonate might induce "feedback" inhibition of intracellular PLA2, the ability of an intracellular phospholipase inhibitor (ONO-RS-082; Biomol, Plymouth, PA) to blunt hypoxic damage was tested. This agent fully reproduced the cytoprotective effect of PLA2. It was concluded that: (1) PLA2-induced cytoprotection is relatively specific for ATP depletion injury; (2) it is dependent on, but not explained by, maintenance of NaCl and Ca2+ gradients; (3) it does not require Na,K-ATPase activity or cytoskeletal integrity for its expression; and (4) extracellular PLA2, via arachidonate release, may cause feedback inhibition of intracellular PLA2, thereby protecting critical intracellular targets from attack.
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PMID:Phospholipase A2-induced cytoprotection of proximal tubules: potential determinants and specificity for ATP depletion-mediated injury. 880 11

We have investigated the effects of cyclosporin A (CsA, 3-50 ng/ml) in combination with the riminophenazine agents clofazimine and B669 (60-500 ng/ml) on the mitogen- and alloantigen-activated proliferative responses of human mononuclear leukocytes (MNL), as well as on the phospholipase A2 and Na+, K+- adenosine triphosphatase activities of these cells. When used in combination these agents caused inhibition of the proliferative responses of both mitogen- and alloantigen-activated MNL which was at least additive. Combinations of CsA with the riminophenazines also caused augmentative activation of PLA2 and inhibition of Na+, K+-ATPase. The inhibitory effects of these agents, both individually and in combination, on the Na+, K+-ATPase and proliferative responses of MNL were neutralized by the membrane-stabilizing, lysophospholipid complex-forming agent alpha-tocopherol (vitamin E, 20 microgram/ml). These observations suggest that combinations of CsA with riminophenazines cause interactive enhancement of the activity of PLA2 in MNL leading to lysophospholipid-mediated inactivation of Na+, K+-ATPase and consequent inhibition of the proliferative responses of these cells. In the therapeutic setting combinations of these agents may enable reduction in the dose of CsA required to achieve meaningful immunosuppression with a consequent decrease in the risk of chemotherapy-related organ toxicity.
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PMID:Augmentative inhibition of lymphocyte proliferation by cyclosporin A combined with the riminophenazine compounds clofazimine and B669. 884 96

Dopamine decreases tubular sodium reabsorption in part by inhibition of Na+,K(+)-ATPase activity in renal proximal tubules. The signaling mechanism involved in dopamine-mediated inhibition of Na+,K(+)-ATPase is known to be defective in spontaneously hypertensive animals. The present study was designed to evaluate the role of phospholipase A2 (PLA2) and its metabolic pathway in dopamine-induced inhibition of Na+,K(+)-ATPase in renal proximal tubules from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Renal proximal tubular suspensions were prepared and Na+,K(+)-ATPase activity was measured as ouabain-sensitive adenosine triphosphate hydrolysis. Dopamine inhibited Na+,K(+)-ATPase activity in a concentration (1 nM-10 microM)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 microM)-induced inhibition of Na+,K(+)-ATPase activity in WKY rats was significantly blocked by mepacrine (10 microM), a PLA2 inhibitor, suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na+,K(+)-ATPase. Arachidonic acid (a product released by PLA2 action) inhibited Na+,K(+)-ATPase in a concentration-dependent (1-100 microM) manner in WKY rats while the inhibition in SHR was significantly attenuated (IC50: 7.5 and 80 microM in WKY rats and SHR, respectively). Furthermore, lower concentrations of arachidonic acid stimulated (30% at 1 microM) Na+,K(+)-ATPase activity in SHR. This suggests a defect in the metabolism of arachidonic acid in SHR. Proadifen (10 microM), an inhibitor of cytochrome P-450 monoxygenase (an arachidonic acid metabolizing enzyme) significantly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na+,K(+)-ATPase between WKY rats and SHR. These data suggest that PLA2 is involved in dopamine-induced inhibition of Na+,K(+)-ATPase and altered arachidonic acid metabolism may contribute to reduced dopaminergic inhibition of Na+,K(+)-ATPase activity in spontaneously hypertensive rats.
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PMID:Altered arachidonic acid metabolism contributes to the failure of dopamine to inhibit Na+,K(+)-ATPase in kidney of spontaneously hypertensive rats. 888 79

The treatment of aspirinated platelets with the endomembrane Ca(2+)-ATPase inhibitor thapsigargin (Tg) induces a large increase in cytosolic pH (pH1), as measured with the intracellular fluorescent indicator 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein. In contrast, Tg induces a decrease in pH1 in the presence of the Na+/H+ exchanger inhibitor 5-(N,N-hexamethylene)-amiloride (NHA). Both effects are inhibited if the cytosolic free Ca2+ concentration ([Ca2+]1) is chelated by loading with bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetra-acetoxymethyl ester (BAPTA-AM). Without BAPTA, the pH effects are inhibited in the presence of BSA or the phospholipase A2 inhibitor oleoyloxyethylphosphocholine. These observations are consistent with the Tg-induced pH effects being mediated at least in part by the release of arachidonic acid (ArA) on activation of phospholipase A2 by the increased [Ca2+]1. Exogenous ArA promotes a rapid decrease in pH1 in platelets suspended in a high-[Na+] medium, and an increase in pH1 if platelets are depolarized by suspension in a high-[K+] medium in the presence of valinomycin and the external pH is increased to 7.9. The protonophore carbonyl cyanide p-trifluoromethoxy-phenylhydrazone (FCCP) behaves like ArA, although ArA is not a protonophore. It is concluded that ArA activates a proton conductance across the plasma membrane. The latter is inhibited by La3+. In high-[Na+] media, the pH1 previously decreased by ArA recovers rapidly on removal of ArA with BSA. The effect is prevented by NHA. The recovery after BSA is much slower if FCCP rather than ArA is used to decrease pH1, but it is fast again with both ArA and FCCP. Furthermore, pH1 previously decreased by ArA also recovers readily on inhibition of the ArA-activated H+ conductance with La3+, and the effect is NHA-sensitive. When pH1 is decreased with the K+/H+ ionophore nigericin, a rapid recovery is activated by ArA followed by BSA (but not by BSA alone). The effect is independent of Ca2+ and protein kinase C. It is concluded that ArA, besides activating the H+ conductance, also acts as an activator of the Na+/H+ exchanger.
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PMID:Arachidonic acid activates a proton conductance pathway and the Na+/H+ exchanger in platelets. 891 96

This study was designed to specify the toxicity of amiodarone toward mouse pulmonary endothelial cells in comparison with that of another cationic amphiphilic drug, i.e., mianserin. These examinations were performed in the absence and presence of mouse alveolar macrophages under transmembrane co-culture or in direct contact with the endothelial cells to assess the contribution of macrophages to the toxicities toward the endothelial cells. As a result of 24-hr treatment, amiodarone caused a decrease in cell viability, in H(+)-ATPase, acid sphingomyelinase, and acid phospholipase A2 activities, and in neutral red uptake, and an increase in permeability of the endothelial cells. Because the magnitude of changes in the endothelial cells was the greatest under direct contact with macrophages, and was the mildest without macrophages, macrophages were considered to enhance the toxicity of amiodarone toward the endothelial cells. Additionally, the toxic effect of amiodarone on the cells was depressed by pretreatment of them with docosahexaenoic acid (DHA) or alpha-tocopherol for 2 days and co-treatment with these agents for 1 day, but not with prednisolone or indomethacin co-treatment. DHA and alpha-tocopherol protected endothelial cells from the toxicity of amiodarone. The effect was more potent for DHA than alpha-tocopherol.
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PMID:Toxicity of amiodarone on mouse pulmonary endothelial cells cultured with or without alveolar macrophages. 895 50

1. The effects of angiotensin II (AngII) on water and electrolyte transport are biphasic and dose-dependent, such that low concentrations (10(-12) to 10(-9) mol/L) stimulate reabsorption and high concentrations (10(-7) to 10(-6) mol/L) inhibit reabsorption. Similar dose-response relationships have been obtained for luminal and peritubular addition of AngII. 2. The cellular responses to AngII are mediated via AT1 receptors coupled via G-regulatory proteins to several possible signal transduction pathways. These include the inhibition of adenylyl cyclase, activation of phospholipases A2, C or D and Ca2+ release in response to inositol-1,4,5,-triphosphate or following Ca2+ channel opening induced by the arachidonic acid metabolite 5,6,-epoxy-eicosatrienoic acid. In the brush border membrane, transduction of the AngII signal involves phospholipase A2, but does not require second messengers. 3. Angiotensin II affects transepithelial sodium transport by modulation of Na+/H+ exchange at the luminal membrane and Na+/HCO3 cotransport, Na+/K(+)-ATPase activity and K+ conductance at the basolateral membrane. 4. Atrial natriuretic factor (ANF) does not appear to affect proximal tubular sodium transport directly, but acts via specific receptors on the basolateral and brush border membranes to raise intracellular cGMP levels and inhibit AngII-stimulated transport. 5. It is concluded that there is a receptor-mediated action of ANF on proximal tubule reabsorption acting via elevation of cGMP to inhibit AngII-stimulated sodium transport. This effect is exerted by peptides delivered at both luminal and peritubular sides of the epithelium and provides a basis for the modulation by ANF of proximal glomerulotubular balance. The evidence reviewed supports the concept that in the proximal tubule, AngII and ANF act antagonistically in their roles as regulators of extracellular fluid volume.
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PMID:Regulation of renal tubular sodium transport by angiotensin II and atrial natriuretic factor. 899 49

The trivalent cation aluminum can cause chronic cytotoxicity in plants, animals and microorganisms. It has been suggested that Al interaction with cell membranes and enzyme metal binding sites may be involved in Al cytotoxicity. In this study, the binding of Al to microsomes and liposomes was found to be lipid dependent with the signal transduction element phosphatidylinositol-4,5-bisphosphate having the highest affinity for Al with an Al:lipid stoichiometry of 1:1. Al binding was only reduced in the presence of high concentrations of Ca2+ (> 1 mM). Both citrate and, to a lesser extent, malate were capable of preventing Al lipid binding, which is consistent with the involvement of these organic acids in a recently described Al detoxification mechanism in plants. The effects of AICl3, Al-citrate and ZnSO4 on metal-dependent enzyme activities (enolase, pyruvate kinase, H+-ATPase, myosin, Calpain, proteinase K, phospholipase A2 and arginase) was assayed in vitro. While Zn2+ was capable of inhibiting all the enzymes except the H+-ATPase, AlCl3 and Al-citrate had minimal effects except for with phospholipase A2 where an interaction with AlCl3 occurred. However, this could be negated by the addition of citrate. The results indicate that, contrary to current hypotheses, the toxic mode of Al is not through an interaction with enzymatic catalytic metal binding sites but may be through the interaction with specific membrane lipids.
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PMID:Aluminum interaction with plasma membrane lipids and enzyme metal binding sites and its potential role in Al cytotoxicity. 900 May 12

The specific sensitivity of the isoforms of the rat brain Na+,K(+)-ATPase catalytic subunit to phospholipase A2 (PL A2) from Naja naja oxiana venom has been estimated on the basis of changes in the two-component dose response curve of ouabain inhibition of Na+,K(+)-ATPase activity. Moderate Na+,K(+)-ATPase inactivation of PL A2 is accompanied by a decrease of the apparent affinity for ouabain in comparison with the untreated enzyme without any significant changes in the isoform activity ratio in the preparation. This effect is eliminated by washing of the preparation with serum albumin and seems to be mediated by the effect of free fatty acids on the enzyme. At a high level of Na+,K(+)-ATPase inactivation, the alpha-isoforms is inactivated more rapidly than the alpha (+)-isoform.
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PMID:[Effect of phospholipase A2 from Naja naja oxiana venom on activity of Na+,K+-ATPase isoenzymes in rat brain]. 901 Dec 52

Dopamine-induced natriuretic response which results from the activation of tubular dopamine1 (DA1) receptors is diminished in spontaneously hypertensive rats (SHR). This may be a result of alterations occurring at the receptor level and within the cellular signaling pathway which ultimately causes inhibition of Na+, K(+)-ATPase. There have been reports showing that DA1 receptor induced inhibition of Na+, K(+)-ATPase is abolished in SHR which is due to a decreased activation of PLC and PKC by dopamine. Of the mechanisms, adenylyl cyclase and phospholipase C are two known enzymes linked to DA1 receptors via G proteins. Furthermore, the involvement of phospholipase A2 (PLA2) has also been reported in this process. However, the site of defect in DA1 receptor signaling pathway in SHR is still not well understood. This report will (i) review the coupling of DA1 receptor with G proteins and their levels in Wistar Kyoto (WKY) rats and SHR and (ii) discuss studies dealing with the role of PLA2 in dopamine-induced inhibition of Na+, K(+)-ATPase in WKY rat and SHR kidneys. Fenoldopam, DA1 receptor selective agonist stimulated [35S]GTP gamma S binding in a concentration (10(-9)-10(-4) M)-dependent manner in WKY rats which was attenuated in SHR. Fenoldopam (10 microM)-induced stimulation of [35S]GTP gamma S binding was significantly reduced by a DA1 receptor selective antagonist, SCH 23390 suggesting the involvement of DA1 receptor. Furthermore, the specific antipeptides Gs alpha, and Gq/11 alpha significantly blocked fenoldopam-stimulation of [35S]GTP gamma S binding suggesting the coupling of DA1 receptor with both the G proteins. Western analysis revealed a significant decrease in Gq/11 alpha but no changes in Gs alpha in SHR compared to WKY rats. Dopamine inhibited Na+, K(+)-ATPase activity in a concentration (10(-9)-10(-5) M)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 microM)-induced inhibition in Na+, K(+)-ATPase activity was significantly blocked by mepacrine (a PLA2 inhibitor) suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na+, K(+)-ATPase. Arachidonic acid (AA), a PLA2 product, inhibited Na+, K(+)-ATPase in a concentration (1-100 microM)-dependent manner in WKY rats while the inhibition in SHR was significantly attenuated (IC50: 7.5 microM in WKY and 80 microM in SHR). Furthermore, lower concentration (1 microM) of AA stimulated the enzyme activity in SHR. This suggests a defect in the metabolism of AA in SHR. Proadifen (10 microM), an inhibitor of cytochrome P-450 monoxygenase (an arachidonic acid metabolizing enzyme) significantly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na+, K(+)-ATPase between WKY rats and SHR. These data suggest that (i) the reduced activation of G proteins following DA1 receptor stimulation, (ii) reduced amount of Gq/11 alpha and (iii) a defect in the AA metabolism may be responsible for the reduced dopaminergic inhibition of sodium pump activity and a diminished natriuretic response to dopamine in SHR.
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PMID:Dopamine-1 receptor G-protein coupling and the involvement of phospholipase A2 in dopamine-1 receptor mediated cellular signaling mechanisms in the proximal tubules of SHR. 902 41

It is well documented that the activity of Na+,K+-ATPase can be inhibited by the arachidonic acid metabolite, 20-hydroxyeicosa-tetraenoic acid (20 HETE). Evidence is presented here that this effect is mediated by protein kinase C (PKC). PKC inhibitors abolished 20 HETE inhibition of rat Na+,K+-ATPase in renal tubular cells. 20 HETE caused translocation of PKC alpha from cytoplasm to membrane in COS cells. It also inhibited Na+,K+-ATPase activity in COS cells transfected with rat wild-type renal Na+,K+-ATPase alpha1 subunit, but not in cells transfected with Na+,K+-ATPase alpha1, where the PKC phosphorylation site, serine 23, had been mutated to alanine. PKC-induced phosphorylation of rat renal Na+,K+-ATPase, as well as of histone was strongly enhanced by 20 HETE at the physiologic calcium concentration of 1.3 microM, but not at the calcium concentration of 200 microM. The results indicate that phospholipase A2-arachidonic acid-20 HETE pathway can exert important biological effects via activation of PKC and that this effect may occur in the absence of a rise in intracellular calcium.
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PMID:20-Hydroxyeicosa-tetraenoic acid (20 HETE) activates protein kinase C. Role in regulation of rat renal Na+,K+-ATPase. 907 30


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