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)

1. We have studied whether a nucleotide receptor mediates the effects of extracellular ATP and UTP on phosphatidylcholine metabolism in rat cultured glomerular mesangial cells. 2. ATP and UTP stimulated a biphasic 1,2-diacylglycerol (DAG) formation in [3H]-arachidonic acid-labelled mesangial cells. In contrast, in cells labelled with [3H]-myristic acid, a tracer that preferentially marks phosphatidylcholine, both nucleotides induced a delayed monophasic production of DAG with a concomitant increase in phosphatidic acid and choline formation. 3. A phospholipase D-mediated phosphatidylcholine hydrolysis was further suggested by the observation that ATP and UTP stimulate the accumulation of phosphatidylethanol, when ethanol was added to mesangial cells. 4. The rank order of potency of a series of nucleotide analogues for stimulation of phosphatidylethanol formation was UTP = ATP > ITP > ATP gamma S > beta gamma-imido-ATP = ADP > 2-methylthio-ATP = beta gamma-methylene-ATP = ADP beta S, while AMP, adenosine, CTP and GTP were inactive, indicating the presence of a nucleotide receptor. 5. Elevation of cytosolic free Ca2+ by the calcium ionophore A23187 (1 microM) or the Ca(2+)-ATPase inhibitor, thapsigargin (200 nM) slightly increased phosphatidylethanol formation. However, chelation of cytosolic Ca2+ with high concentrations of Quin 2 did not attenuate ATP- and UTP-induced phosphatidylethanol production, thus suggesting that Ca2+ is not crucially involved in agonist-stimulated phospholipase D activation. 6. The protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), but not the biologically inactive 4 alpha-phorbol 12,13-didecanoate, increased phospholipase D activity in mesangial cells, suggesting that PKC may mediate nucleotide-induced phosphatidylcholine hydrolysis. 7. Down-regulation of PKC-alpha and -delta isoenzymes by 8 h PMA treatment still resulted in full phospholipase D activation. In contrast, a 24 h treatment of mesangial cells with PMA, a regimen that also causes depletion of PKC-epsilon, markedly attenuated nucleotide-evoked phosphatidylethanol formation. In addition, the selective PKC inhibitor, calphostin C attenuated ATP- and UTP-induced phosphatidylethanol production.8. In summary, these data suggest that extracellular ATP and UTP use a common nucleotide receptor to activate phospholipase D-mediated phosphatidylcholine hydrolysis. Stimulation of phospholipase D appears to involve the PKC-epsilon isoenzyme, activated by DAG derived from phosphoinositide hydrolysis by phospholipase C.
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PMID:Extracellular ATP and UTP activation of phospholipase D is mediated by protein kinase C-epsilon in rat renal mesangial cells. 824 60

Synthetic lipopeptides activate superoxide-anion (O2-) formation in human neutrophils in a pertussis-toxin (PTX)-sensitive manner, suggesting the involvement of G-proteins of the Gi family in the signal-transduction pathway. We compared G-protein activation by lipopeptides and the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) in dibutyryl-cyclic-AMP-differentiated HL-60 cells. The lipopeptide (2S)-2-palmitoylamino-6-palmitoyloxymethyl-7-palmitoyloxy heptanoyl-SK4 (Pam3AhhSK4) and fMLP activated high-affinity GTPase, i.e. the enzymic activity of G-protein alpha-subunits, in HL-60 membranes in a time- and protein-dependent manner, but they had no effect on Mg(2+)-ATPase and Na+/K(+)-ATPase. Pam3AhhSK4 and fMLP increased Vmax. of GTP hydrolysis. Pam3AhhSK4 activated GTP hydrolysis with half-maximal and maximal effects at about 2 microM and 10 microM respectively. Other lipopeptides activated GTP hydrolysis as well. Lipopeptides were less effective than fMLP to activate GTPase. In membranes from PTX-treated cells, the stimulatory effects of lipopeptides and fMLP on GTPase were abolished. In N-ethylmaleimide-treated membranes, the relative stimulatory effect of Pam3AhhSK4 on GTP hydrolysis was enhanced, whereas that of fMLP was diminished. fMLP and Pam3AhhSK4 activated GTPase in an over-additive manner in N-ethylmaleimide-treated membranes. Unlike fMLP, Pam3AhhSK4 did not enhance incorporation of GTP azidoanilide into, and cholera-toxin-catalysed ADP-ribosylation of Gi-protein alpha-subunits in, HL-60 membranes and did not induce rises in cytosolic Ca2+ concentration. Pam3AhhSK4 and fMLP stimulated phosphatidic acid formation in a PTX-sensitive manner. Pam3AhhSK4 itself did not activate O2- formation, but potentiated the stimulatory effects of fMLP. Our data suggest that (i) lipopeptides activate the GTPase of Gi-proteins, (ii) lipopeptides and fMLP activate Gi-proteins differently, (iii) lipopeptides stimulate phospholipase D via Gi-proteins, and (iv) phosphatidic acid formation is not sufficient for activation of O2- formation.
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PMID:Lipopeptides activate Gi-proteins in dibutyryl cyclic AMP-differentiated HL-60 cells. 825 Aug 50

The role of Ca2+ and protein kinase C (PKC) in the regulation of phosphatidylcholine-hydrolyzing phospholipase D (PLD) was investigated in angiotensin II-stimulated mesangial cells. Elevation of cytosolic free Ca2+ by the calcium ionophore, A23187, or the Ca(2+)-ATPase inhibitor, thapsigargin, slightly increased PLD-stimulated phosphatidylethanol formation. However, chelation of cytosolic Ca2+ with high concentrations of quin 2 did not attenuate angiotensin II-induced phosphatidylethanol production, thus suggesting that Ca2+ is not crucially involved in agonist-stimulated PLD activation. Stimulation of PKC by phorbol esters increased PLD activity in mesangial cells. Down-regulation of PKC-alpha and -delta isoenzymes by 8 h phorbol ester treatment still resulted in full PLD activation. In contrast, a 24 h treatment of mesangial cells with phorbol ester, a regimen that also causes depletion of PKC-epsilon, abolished angiotensin II-evoked phosphatidylethanol formation. In addition, the selective PKC inhibitor, calphostin C, attenuated hormone-induced PLD activity. In summary, these data suggest that angiotensin II stimulation of phospholipase D appears to involve the PKC-epsilon isoenzyme, activated by DAG derived from phosphoinositide hydrolysis.
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PMID:A role for protein kinase C-epsilon in angiotensin II stimulation of phospholipase D in rat renal mesangial cells. 839 15

Phosphatidylethanol is formed by "transphosphatidylation' of phospholipids with ethanol catalysed by phospholipase D and can be accumulated in the plasma membrane of mammalian cells after treatment of animals with ethanol. In the present work we show that phosphatidylalcohols, such as phosphatidylethanol and phosphatidylbutanol, produced a twofold stimulation of the Ca(2+)-ATPase activity of human erythrocytes. This stimulation occurs with the purified, solubilized enzyme as well as with ghost preparations, where the enzyme is in its natural lipidic environment and is different to that obtained with other acidic phospholipids such as phosphatidylserine. Addition of either phosphatidylserine, phosphatidylethanol or phosphatidylbutanol to the purified Ca(2+)-ATPase, or to ghosts preparations, increased the affinity of the enzyme for Ca2+ and the maximal velocity of the reaction as compared with controls in the absence of acidic phospholipids. However, in contrast with what occurs with phosphatidylserine, simultaneous addition of phosphatidyl-alcohols and calmodulin increased the affinity of the enzyme for Ca2+ to a greater extent than each added separately. When ethanol was added to either the purified erythrocyte Ca(2+)-ATPase or to erythrocyte-ghost preparations in the presence of acidic phospholipids, an additive effect was observed. There was an increase in the affinity for Ca2+ and in the maximal velocity of the reaction, well above the values obtained with ethanol or with the acidic phospholipids tested separately. These findings could have pharmacological importance. It is conceivable that the decrease in the intracellular Ca(2+) concentration that has been reported in erythrocytes as a result of ethanol intoxication could be due to the stimulation of the Ca(2+)-ATPase by the accumulated phosphatidylethanol, to a direct effect of ethanol on the enzyme or to an additive combination of both.
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PMID:Phosphatidylethanol stimulates the plasma-membrane calcium pump from human erythrocytes. 876 Mar 85

The actions of TSH, ATP, the ionophore A23187, the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin, and phorbol dibutyrate (PDBu) on 3H-cytidine-monophosphate phosphatidic acid (3H-CMP-PA) accumulation were studied in human thyroid slices to evaluate PA generation and inositol recycling towards phosphatidyl-inositol synthesis. The effects of the same agonists also were measured on phosphatidylbutanol (PtdBut) generation in 3H-palmitate or 3H-myristate prelabeled slices to assess the activity of phospholipase D (PLD). The phospholipid target of this PLD was determined on 3H-choline prelabeled human thyroid slices by measuring 3H-choline release in incubation medium and slices and 3H-choline incorporation in phospholipids. TSH (10 U/L) stimulated 3H-CMP-PA accumulation in an LiCl-and propranolol-insensitive way, as well as 2H-fatty acids incorporation into PA, diacylglycerol, and phosphatidylcholine (PtdCho) with on evidence of dose-dependent effects and had no detectable action on PLD activity. The effects of TSH were not reproduced by Bu2cAMP or forskolin. Thapsigargin and A23187 both increased CMP-PA accumulation and PtdBut generation, whereas ATP only stimulated PLD activity. The phorbol ester PDBu (5 x 10(-7) mol/L) increased PtdBut formation and 3-H-fatty acid incorporation into PtdCho, but had no effect on CMP-PA generation. Staurosporine (STSP) (5 x 10(-6) mol/L), a nonspecific inhibitor of protein kinase C, unexpectedly reproduced the effects of PDBu. The increase of 3H-choline in slices' supernatant and the decrease of 3H-choline-labeled PtdCho induced by PDBu, ATP, thapsigargin, and STSP indicate that the activated PLD hydrolyzed PtdCho. We suggest that the PA generation induced by PLD stimulation could contribute to the stimulated H2O2 formation and iodide organification observed with the agonists inducing PtdBut accumulation. Indeed, Bu2cAMP and forskolin, known to decrease iodide organification in human thyroid, inhibited the PLD stimulation induced by ATP and PDBu. In cultured dog thyrocytes, phorbol esters, and STSP induced DNA synthesis and dedifferentiation, whereas thapsigargin inhibited TSH-induced growth and killed phorbol esters stimulated cells, suggesting a positive role of PLD stimulation towards dedifferentiated growth and of simultaneously raised [Ca2+)i and stimulated protein kinase C-PLD towards growth arrest and cellular death.
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PMID:Regulation and metabolic role of phospholipase D activity in human thyroid and cultured dog thyrocytes. 885 96

Bacterial lipopolysaccharide (LPS)-induced exocytosis is one of the primary immune responses of the Limulus granulocyte (GR). Exocytosis can be mediated by guanine nucleotide-binding protein (G-protein)-linked surface receptors that activate phospholipase C (PLC) to produce inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular Ca2+ ([Ca2+]i), which can lead to exocytosis. We used activators and inhibitors of known signal transduction pathways to investigate the signaling pathway responsible for LPS-induced exocytosis in the GR. These compounds have been shown to similarly effect pathways in vertebrate and invertebrate systems and this assumption is made here. Pretreatment of GRs with cholera and pertussis toxins, which modulate G-proteins, and U73122, which inhibits PLC, inhibited LPS-induced exocytosis, but pretreatment with the tyrosine kinase inhibitor herbimycin did not. In contrast, exocytosis was induced with fluoride (a G-protein activator) and thapsigargin with Mg2+ (an inhibitor of endomembranous Ca(2+)-ATPase). Exocytosis was not induced by phorbol ester, which mimics DAG to activate protein kinase C (PKC) and it was not effected by ethanol or chelerythrine, which inhibit phospholipase D and PKC, respectively. Microinjection of GRs with different concentrations of IP3, an IP3 analog (DL-2,3,6,trideoxy-myo-inositol 1,4,5-triphosphate), Mg2+, or Ca2+ induced different percentages of exocytosis in individual cells, while HEPES buffer did not. Microfluorometric analysis of intracellular Mg2+ ([Mg2+]i) and [Ca2+]i, using the dyes Mag Fura-2AM and Calcium Green 5N, respectively, revealed [Mg2+]i and [Ca2+]i fluxes during LPS-induced exocytosis. This study suggests that LPS induces exocytosis in the Limulus GR through activation of G-protein-coupled receptors, which stimulate the IP3 signaling pathway to induce both [Ca2+]i and [Mg2+]i fluxes to facilitate vesicular and plasma membrane fusion. This is the first demonstration of the signal transduction pathway responsible for the primary immune response of the GR.
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PMID:Signal transduction during exocytosis in Limulus polyphemus granulocytes. 901 85

Preparation of kidney proximal tubules in suspension allows the study of receptor-mediated endocytosis, protein reabsorption, and traffic of endosomal vesicles. The study of tubular protein transport in vitro coupled with that of the function of endosomal preparation offers a unique opportunity to investigate a receptor-mediated endocytosis pathway under physiological and pathological conditions. We assume that receptor-mediated endocytosis of albumin in kidney proximal tubules in situ and in vitro can be regulated, on the one hand, by the components of the acidification machinery (V-type H+-ATPase, Cl(-)-channel and Na+/H+-exchanger), giving rise to formation and dissipation of a proton gradient in endosomal vesicles, and, on the other hand, by small GTPases of the ADP-ribosylation factor (Arf)-family. In this paper we thus analyze the recent advances of the studies of cellular and molecular mechanisms underlying the identification, localization, and function of the acidification machinery (V-type H+-ATPase, Cl(-)-channel) as well as Arf-family small GTPases and phospholipase D in the endocytotic pathway of kidney proximal tubules. Also, we explore the possible functional interaction between the acidification machinery and Arf-family small GTPases. Finally, we propose the hypothesis of the regulation of translocation of Arf-family small GTPases by an endosomal acidification process and its role during receptor-mediated endocytosis in kidney proximal tubules. The results of this study will not only enhance our understanding of the receptor-mediated endocytosis pathway in kidney proximal tubules under physiological conditions but will also have important implications with respect to the functional consequences under some pathological circumstances. Furthermore, it may suggest novel targets and approaches in the prevention and treatment of various diseases (cystic fibrosis, Dent's disease, diabetes and autosomal dominant polycystic kidney disease).
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PMID:Receptor-mediated endocytosis in kidney proximal tubules: recent advances and hypothesis. 958 51

Cancer chemotherapy often fails because of the development of tumors which are resistant to most commonly used cytotoxic drugs. This phenomenon, multidrug resistance (MDR), is usually mediated by overexpression of P-glycoprotein (P-gp), an ATPase that pumps out the drugs used in chemotherapy, thereby preventing their accumulation in cancer cells and greatly reducing their cytotoxic efficacy. A large body of work indicates that MDR is associated also with marked changes in membrane lipid composition. Most notably, elevated levels of cholesterol, glycosphingolipids (e.g., glucosylceramide), and sphingomyelin have been reported. These lipids are enriched in caveolae and in membrane microdomains termed detergent-insoluble glycosphingolipid-enriched complexes (DIGs). Recently we demonstrated that in multidrug-resistant tumor cells there is a dramatic increase in the number of caveolae and in the level of caveolin-1, an essential structural constituent of caveolae. Another constituent of membrane microdomains, phospholipase D, is also elevated in MDR cells. These findings may be related to the fact that a significant fraction of cellular P-gp is associated with caveolin-rich membrane domains. The possible role of DIGs and caveolae in the acquisition and/or maintenance of the multidrug resistant phenotype is discussed.
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PMID:Changes in membrane microdomains and caveolae constituents in multidrug-resistant cancer cells. 1041 89

Adenosine diphosphate-ribosylation factor (Arf) proteins are members of the Arf arm of the Ras superfamily of guanosine triphosphate (GTP)-binding proteins. Arfs are named for their activity as cofactors for cholera toxin-catalyzed adenosine diphosphate-ribosylation of the heterotrimeric G protein Gs. Physiologically, Arfs regulate membrane traffic and the actin cytoskeleton. Arfs function both constitutively within the secretory pathway and as targets of signal transduction in the cell periphery. In each case, the controlled binding and hydrolysis of GTP is critical to Arf function. The activities of some guanine nucleotide exchange factors (GEFs) and guanosine triphosphatase (GTPase)-activating proteins (GAPs) are stimulated by phosphoinositides, including phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 4,5-bisphosphate (PIP2), and phosphatidic acid (PA), likely providing both a means to respond to regulatory signals and a mechanism to coordinate GTP binding and hydrolysis. Arfs affect membrane traffic in part by recruiting coat proteins, including COPI and clathrin adaptor complexes, to membranes. However, Arf function likely involves many additional biochemical activities. Arf activates phospholipase D and phosphatidylinositol 4-phosphate 5-kinase with the consequent production of PA and PIP2, respectively. In addition to mediating Arf's effects on membrane traffic and the actin cytoskeleton, PA and PIP2 are involved in the regulation of Arf. Arf also works with Rho family proteins to affect the actin cytoskeleton. Several Arf-binding proteins suspected to be effectors have been identified in two-hybrid screens. Arf-dependent biochemical activities, actin cytoskeleton changes, and membrane trafficking may be integrally related. Understanding Arf's role in complex cellular functions such as protein secretion or cell movement will involve a description of the temporal and spatial coordination of these multiple Arf-dependent events.
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PMID:Molecular aspects of the cellular activities of ADP-ribosylation factors. 1175 22

Hyperosmotic stress induces the rapid formation of phosphatidic acid (PA) in Chlamydomonas moewusii via the activation of two signalling pathways: phospholipase D (PLD) and phospholipase C (PLC), the latter in combination with diacylglycerol kinase (DGK) (Munnik et al., 2000). A concomitant increase in cell Ca(2+) becomes manifest as deflagellation. When KCl was used as osmoticum we found that two concentration ranges activated deflagellation: one between 50 and 100 mm and another above 200 mm. Deflagellation in low KCl concentrations was complete within 30 sec whereas in high concentrations it took 5 min. PLC was not activated, as it was by high KCl concentrations that cause hyperosmotic stress. Moreover PLD was activated more strongly by low than by high KCl concentrations. Potassium was the most potent monovalent cation based on the induction of deflagellation and the formation of PA and PBut. During treatment, the external medium acidified, indicating an increase in H(+)-ATPase activity in order to re-establish the membrane potential. Activation of PLD and deflagellation at low KCl concentrations were abrogated by treatment with La(3+), Gd(3+) and EGTA, indicating the dependency on extracellular Ca(2+). This suggests that low concentrations of KCl depolarize the plasma membrane, resulting in the activation of H(+)-ATPases and opening voltage-dependent Ca(2+) +/- channels, observed as deflagellation and an increase in PLD activity.
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PMID:KCl activates phospholipase D at two different concentration ranges: distinguishing between hyperosmotic stress and membrane depolarization. 1210 Apr 82


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