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PubMed1986

Phosphatidylcholine and cholesterol inhibit phosphatidate-mediated calcium traversal of liposomal bilayers.

Rates of phosphatidic acid- (PA-) mediated Ca2+-traversal are maximal in 'passive bilayers' void of lipid CO and OH groups: dietherphosphatidylcholine (diether-PC) or OH-blocked cholesterol liposomes. Phosphatidylcholine (PC) as bilayer matrix causes 99% inhibition, while 45 mol% cholesterol in passive bilayers inhibits by about 70%. Possibly, the absence of CO and OH groups causes a dehydration of the 'hydrogen belts', i.e., the membrane strata occupied by hydrogen bond acceptors (CO of phospholipids) and donors (OH of cholesterol, sphingosine) and thereby facilitates the formation of dehydrated Ca(PA)2, the ionophoric vehicle; or (our preferred explanation) PC engages in a (non-ionophoric) Ca(PA X PC) complex and thus reduces the concentration of the ionophore, while cholesterol competes with Ca2+ for the CO groups of phosphatidic acid by hydrogen-bonding. The Ca2+-traversal rates realized in bilayers with modified hydrogen belts lend support to the speculation that a Ca(PA)2 ferry may be of physiological importance, e.g., in membranes (such as myelin) containing much ether phospholipid (plasmalogen); and that Ca2+-membrane association and traversal may be controlled by the composition of the hydrogen belts.

Biological Transport↗
PubMed1987

2H-NMR, 31P-NMR and DSC characterization of a novel lipid organization in calcium-dioleoylphosphatidate membranes. Implications for the mechanism of the phosphatidate calcium transmembrane shuttle.

2H-NMR, 31P-NMR and DSC investigations are presented on the structure and dynamics of the Ca2+-dioleoylphosphatidate complex which is formed upon addition of calcium to dispersions of pure dioleoylphosphatidate or of dioleoylphosphatidate in mixtures with dioleoylphosphatidylcholine (DOPC). It is concluded that the phosphate region in the polar headgroup of dioleoylphosphatidate is immobilized, while the oleate chains remain liquid and have increased disorder. In mixtures of dioleoylphosphatidate and DOPC in the presence of calcium a dioleoylphosphatidate-rich phase is segregated, in which the molecular behaviour of phosphatidate is rather similar to that of the pure Ca2+-dioleoylphosphatidate complex. A hypothetical model is proposed for the structure of this complex and this is correlated with the dioleoylphosphatidate-mediated transmembrane transport of calcium (Smaal, E.B., Mandersloot, J.G., De Kruijff, B. and De Gier, J. (1986) Biochim. Biophys. Acta 860, 99-108). Data indicate that this transmembrane shuttle is an inverted organization of phosphatidate molecules enclosing calcium ions in an anhydrous core.

Biological Transport↗
PubMed1978

Characterization of phosphatidate phosphohydrolase activity associated with isolated lamellar bodies.

It has been demonstrated that lamellar bodies isolated from porcine lung have L-alpha-phosphatidate phosphohydrolase (EC 3.1.3.4) activity which cannot be accounted for by microsomal or mitochondrial contamination. Phosphatidate phosphohydrolase activity associated with the lamellar bodies is relatively insensitive to Mg2+ and more heat labile than the activity associated with whole lung microsomes. The enzyme was found to be the most active phosphohydrolase present in isolated lamellar bodies and is inhibited by 5 mM Be2+. Lamellar bodies isolated from human and rat lung tissue were also found to have this activity, and the functional role of the enzyme in lamellar bodies is proposed in relation to glycerophospholipid metabolism.

Animals↗
PubMed1982

Effect of salts on membrane binding and activity of adipocyte phosphatidate phosphohydrolase.

Isosmotic replacement of sucrose in a low ionic strength homogenizing buffer (0.25 M sucrose/1 mM EDTA/1 mM Tris-HCl, pH 7.4) with KCl increased the microsomal and decreased the soluble phosphatidate phosphohydrolase (EC 3.1.3.4) activity of isolated rat fat cells. At 54 mM KCl the microsomal specific activity was increased 6-fold and the soluble activity was decreased to less than one-third. Binding of enzyme was promoted by KCl and NaCl when the once isolated soluble and microsomal fractions were recombined and incubated at 37 degrees C. Half-maximal binding occurred at about 17 mM salt and maximal binding at about 50 mM. The pH optimum of binding was 7.8 in 15 mM Hepes. MgCl2, CaCl2 and spermine prevented desorption of microsomal enzyme at mu molar levels and maximal effects were observed at concentrations below the 1 mM level. At maximum, however, the prevention of desorption was less by these salts than it was by KCl. MgCl2 and spermine also interfered with the effect of KCl. Moderate salt-induced loading of microsomes with the phosphohydrolase (specific activity increased 3.5-fold) increased their ability to incorporate 14C into triacylglycerol from sn-[U-14C]glycerol 3-phosphate while a high loading (specific activity increased 6-fold) had no effect or even suppressed it. The results are discussed in relation to a role of translocation of phosphatidate phosphohydrolase in glyceride biosynthesis and its control.

Adipose Tissue↗
PubMed1986

Isolation and characterization of multiple forms of Mg2+-dependent phosphatidate phosphohydrolase from rat adipose cytosol.

In the present studies, we have made several unique observations. First, we have shown that cytosolic phosphatidate phosphohydrolase from adipose tissue subjected to butyl-agarose chromatography was resolved into four different components. These components, designated as passthrough (PT), D150, D250 and E, were present in the proportions of 51:7:24:16, respectively, in the rat adipose cytosol. Comparison of the properties of these components revealed some similar properties, and also several differences. These components showed the same pH optimum, required Mg2+ for activity and were inhibited by N-ethylmaleimide, indicating a requirement of active sulfhydryl groups for activity. These components differed from one another with respect to hydrophobicity, sedimentation behavior, Stokes diameter, Km values, thermolability and susceptibility to proteinase treatment. Second, we have shown that each component of this system was associated with lipids which were found to be essential for the catalytic activity. Perturbation of this association by organic solvent or by adding excess amounts of exogenous lipids resulted in the loss of enzyme activity. Finally, we analyzed lipid composition of individual components. These studies suggest that the multi-component system of Mg2+-dependent phosphatidate phosphohydrolase may be a part of the cytomembrane network.

Adipose Tissue↗
PubMed1987

Effect of spermine on the translocation of Mg2+-dependent phosphatidate phosphohydrolase.

Adipose cytosol treated with spermine showed an aggregation of a cytosolic component which was isolated by centrifugation at 16,000 X g for 20 min. The resultant pellet contained 10% of protein, 40% of lipid and over 75-97% of Mg2+-dependent phosphatidate phosphohydrolase and CTP:phosphocholine cytidylyltransferase activities present in the original cytosol. The specific activities of these enzymes increased 4-fold by the spermine treatment. Characterization of lipids in this component indicated the presence of mainly phospholipids. These studies suggest that the interaction between spermine, the cytosolic component and microsomal membranes may be involved in the translocation of Mg2+-dependent phosphatidate phosphohydrolase.

Adipose Tissue↗
PubMed1987

Stimulatory effect of mevinolin on rat liver phosphatidic acid phosphatase.

The activity of the soluble form of phosphatidic acid phosphatase in rat liver was stimulated about 2.5-fold by inclusion of mevinolin, a competitive hydroxymethylglutaryl-CoA reductase inhibitor, in the diet (0.1%). The stimulatory effect of mevinolin was present also after dietary addition of cholestyramine (5%) or intraperitoneal administration of ethanol. Addition of cholesterol (2%) to the diet totally abolished the stimulation by mevinolin on phosphatidic acid phosphatase. The results support a correlation between the synthesis of the rate-limiting enzyme in cholesterol biosynthesis and the activity of the apparent rate-limiting enzyme in triacylglycerol biosynthesis.

Acid Phosphatase↗
PubMed1992

Comparison of the molecular species patterns of phosphatidic acid, CDP-diacylglycerols and phosphatidylinositol in potato tuber, pea leaf and soya-bean microsomes: consequences for the selectivity of the enzymes catalyzing phosphatidylinositol biosynthesis.

Microsomes prepared from pea leaf, potato tuber or germinated soya-beans, were incubated for 30 min with [14C]glycerol 3-phosphate. In the three tissues, phosphatidic acid (PA), CDP-diacylglycerols (CMP-PA) and phosphatidylinositol (PI) were labelled and could be separated by TLC. After methylation of phosphatidic acid, or treatment of CMP-PA by a nucleotidase, the molecular species composition of the three lipid classes could be determined by radio-HPLC. The similarity observed between the distributions of radioactivity among CMP-PA and PA molecular species, in the three tissues, indicates that the enzyme CTP:PA cytidylyltransferase did not present any selectivity towards any molecular species of PA. In contrast, only two molecular species containing palmitic acid (16:0/18:2 and 16:0/18:3) were labelled in PI whereas labelled PA and CMP-PA contained molecular species possessing stearic acid (18:0/18:2, 18:0/18:3 and 18:0/18:1). This indicates that the enzyme PI-synthase utilizes preferentially those molecular species of CMP-PA containing palmitic acid as substrates. However, mass analyses of PI prepared from the microsomes of the three tissues used in this study, indicated the presence of molecular species containing stearic acid (18:0/18:2 and 18:2/18:2). Except in soya-bean microsomes (where 18:0/18:2-PI represented 16% of total PI), those last molecular species were always present in small amounts.

CDP-Diacylglycerol-Inositol 3-Phosphatidyltransfer↗
PubMed1992

Physical evidence for the presence of two forms of phosphatidate phosphohydrolase in rat liver.

Phosphatidate phosphohydrolase (PAP)-catalysed dephosphorylation of phosphatidic acid to diacylglycerol is an important step in glycerolipid metabolism and cell-signalling. Gel filtration chromatography on Superose 6 and anion-exchange chromatography on Mono Q of rat liver subcellular fractions has provided physical evidence for the presence of two distinct forms of PAP activity. One form was sensitive to inhibition by N-ethylmaleimide (NEM), had an apparent M(r) of 540,000 and was eluted from the anion-exchange column by 0.35 M NaCl, while the other was insensitive to inhibition by NEM, had an apparent M(r) of 240,000 and was eluted from the anion-exchange column by 0.15 M NaCl. Studies on the subcellular distribution of these two enzymes, using 5'-nucleotidase as a plasma membrane marker, demonstrated that the NEM-sensitive form was predominantly cytosolic but translocated to the microsomal membranes in response to oleate. The NEM-insensitive form was predominantly located in the plasma membrane but a small proportion (approx. 10%) of total cell activity was present on the endoplasmic reticulum. The implications of these results for the likely roles of the two different forms of PAP in fatty acid esterification and cell-signalling are discussed.

5'-Nucleotidase↗
PubMed1985

Carbachol stimulation of phosphatidic acid synthesis: competitive inhibition by pirenzepine in synaptosomes from rat cerebral cortex.

Carbachol stimulated phosphatidic acid synthesis in cholinergically enriched synaptosomes from rat cerebral cortex. Increasing concentrations of pirenzepine (10-1000 nM) produced parallel concentration-response curves to carbachol which were shifted to the right. A pA2 value for pirenzepine of 8.4 +/- 0.3 was obtained from Schild analysis. We hypothesize that high affinity pirenzepine binding to M1 receptors is coupled to phosphatidic acid synthesis in the rat cerebral cortex.

Animals↗
PubMed1985

Lyso(bis)phosphatidic acid: a novel source of arachidonic acid for oxidative metabolism by rabbit alveolar macrophages.

To identify the source of arachidonic acid utilized for eicosanoid production, rabbit alveolar macrophages were challenged with 1.0 microM 12-O-tetradecanoylphorbol-13-acetate (TPA) or 3.8 microM Ca+2 ionophore A23187 for 3 h. Upon stimulation with TPA, a loss of [3H]arachidonic acid from phosphatidylcholine, phosphatidylethanolamine, lyso(bis)phosphatidic acid, and phosphatidylserine/phosphatidylinositol was observed. Although calcium ionophore stimulated the liberation of arachidonate solely from phosphatidyl-ethanolamine and phosphatidylcholine, it proved to be a poor stimulus for macrophage-synthesis of eicosanoids. Our evidence suggests that degradation of phosphatidylinositol and lyso(bis)phosphatidic acid induced by TPA yields a source of arachidonate which is the preferred substrate for oxidative metabolism by the cyclooxygenase and lipoxygenase pathways.

Animals↗
PubMed1986

Activation of phosphatidic acid metabolism of human erythrocyte membranes by perfringolysin O.

The effect of perfringolysin O on the lipid metabolism of human erythrocyte membranes was investigated. Erythrocytes were prelabeled with [3H]arachidonic acid and [32P]inorganic phosphate. In the presence of calcium ion(5.5 mM), the effect of perfringolysin O on lipid metabolism was very similar to that of an calcium-ionophore A23187. In the absence of calcium ion, the accumulation of phosphatidic acid and its following decreasing trend were observed during the reaction with the toxin. Such changes were not caused by filipin. These results suggest that perfringolysin O causes the activation of a diglyceride-phosphatidic acid cycle, which might be involved in the calcium transport.

Bacterial Toxins↗
PubMed1987

Stimulation of quiescent 3T3 cells by phosphatidic acid-containing liposomes.

Liposomes containing phosphatidic acid were capable of stimulating DNA synthesis in quiescent Swiss 3T3 cells while liposomes composed of other phospholipids were not. These results show that liposomes, which are usually employed to deliver non-lipid molecules into cells, can themselves have profound effects on cell growth. The possible mechanism of phosphatidic acid-mediated cell stimulation and its relation to other growth factors are discussed.

Animals↗
PubMed1983

Effects of pentobarbital and veratridine on phosphatidylinositol and phosphatidate metabolism in rat parotid acinar cells.

The metabolism of phosphatidylinositol and phosphatidate was studied in isolated rat parotid cells, incubated in a physiological buffer containing [32P]phosphate or [3H]glycerol. Carbamylcholine and epinephrine stimulated 32P incorporation into both of these phospholipids, causing their half-maximal effects at 2 and 0.8 microM respectively. The former concentration is much lower than that anticipated from binding studies. The Hill coefficients for carbamylcholine activation of 32P incorporation were 0.61 +/- 0.05 for phosphatidate and 0.64 +/- 0.05 for phosphatidylinositol. Pentobarbital (0.58 mM) inhibited the increased 32P incorporation caused by 5 microM carbamylcholine but not 100 microM carbamylcholine. Pentobarbital inhibited the incorporation of 3H equally in the presence and absence of epinephrine, indicating that the effect of pentobarbital on 32P incorporation is on turnover and not on de novo synthesis. Veratridine (200 microM) had no effect on phospholipid metabolism in the presence and absence of either carbamylcholine or epinephrine, which contrasts with our previous findings in synaptosomes [J.C. Miller and I. Leung, Biochem. J. 178, 9 (1979)].

Animals↗
PubMed1988

Effect of PCR 4099 on ADP-induced calcium movements and phosphatidic acid production in rat platelets.

Antiplatelet activity of PCR 4099, an analogue of ticlopidine, resides in its specific effect against exogenous as well as released ADP. This study investigated in rat platelets the effects of the drug on ADP-induced shape change, elevation of cytosolic free Ca2+ concentration ([Ca2+]i) and hydrolysis of inositol phospholipids, monitored as [32P]phosphatidic acid formation. Shape change and influx of Ca2+ ions across the plasma membrane were not modified after PCR 4099 administration using aspirin-treated platelets. On the other hand, phosphatidic acid formation and calcium mobilization from internal stores were strongly inhibited. These results suggest that PCR 4099 leaves intact the machinery involved in ADP-induced platelet shape change and influx of calcium ions, but inhibits an early step in the ADP-response coupling leading to inositol phospholipid hydrolysis and aggregation.

Adenosine Diphosphate↗
PubMed1992

Stimulation of phosphatidic acid synthesis in bovine aortic endothelial cells in response to activation of P2-purinergic receptors.

In this study we used the bovine thoracic aorta endothelial cell line AG 4762 and primary bovine aortic endothelial cells to investigate the formation of phosphatidic acid (PA) in response to activation of P2-purinergic receptors. 2-Methylthio ATP (2MeSATP) stimulated the formation of [32P]-PA in bovine aortic endothelial cells labelled with 32P(i) for 2.5 hr. A comparison of the response to other ATP analogues suggests that this was mediated via a P2Y-purinergic receptor. Using various agonists at 30 microM there was a correlation between the formation of [32P]PA and of total inositol phosphates in the presence of lithium. The 2MeSATP-stimulated accumulation of [32P]PA showed an initial high rate, followed by a more sustained slower rate. The initial response was independent of extracellular calcium while the later response was dependent on calcium influx. The protein kinase C stimulator phorbol myristate acetate (PMA) produced only a very small enhancement of [32P]PA accumulation compared to 2MeSATP. The 2MeSATP stimulation of both inositol phosphates and [32P]PA was almost eliminated by the presence of PMA. Using cells prelabelled with [3H]methylcholine 2MeSATP produced only a small non-significant enhancement of [3H]choline formation; PMA by contrast formed a much larger amount of [3H]choline. There was no evidence of a change in [3H]phosphocholine. The dissociation between phospholipase D (PLD) activation and [32P]PA accumulation and the correlation between stimulation of [32P]PA accumulation and phospholipase C (PLC) activation all suggest that, using this protocol for labelling cells, the principle route of the stimulation of formation of [32P]PA is via the activation of PLC followed by metabolism of diacylglycerol (DAG) by DAG kinase. These results show that activation of P2Y-purinergic receptors on aortic endothelial cells leads to the formation of phosphatidic acid and that both PLD and PLC pathways are likely to contribute to this response.

Animals↗
PubMed1990

Influence of alkali metal cations on the transport of calcium by phosphatidate in multi-phase systems.

The effects of alkali metal cations on the rates at which Ca2+ and phosphatidic acid were cotransported from aqueous to hydrocarbon medium were examined. The alkali metal cations remained in the aqueous phase yet specifically influenced the transport of Ca2+ into the hydrocarbon solvent. For the physiological cations, Na+ and K+, there were critical concentration ranges in which small changes in concentration effected sharp changes in transport rates. The maximal rate observed with Na+ was an order of magnitude greater than that with K+; however, unlike Na+, K+ promoted low levels of transport below the critical concentration range. Li+ effected only low levels of transport even at high concentrations, whereas Rb+ and Cs+ induced transport at rates proportional to their concentrations. These results are discussed in terms of a classical ionophore model for the complex composed of a neutral phosphatidic acid dimer bridged by Ca2+.

Biological Transport, Active↗
PubMed1985

Phosphatidic acid phosphatase activity in subcellular fractions of normal and dystrophic human muscle.

Biopsy samples from normal and dystrophic human muscle (Duchenne type) were fractionated by differential centrifugation and microsomes, mitochondria and cytosol were assayed for phosphatidic acid phosphatase (EC 3.1.3.4) and marker enzymes of mitochondria and cytosol. The activity of phosphatidic acid phosphatase was significantly lower in microsomes and higher in cytosol and mitochondria of dystrophic muscle than in the corresponding subcellular fractions of normal muscle. The results support an explanation of earlier findings that there is reduced G3P incorporation into diglycerides and phosphatidylcholine and a qualitative and quantitative change in the amount of phosphatidylcholine in dystrophic microsomes. The possible reasons for the reduction in the activity of only microsomal PA-P-ase were discussed.

Animals↗