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PubMed2002

Structural and topographical characteristics of dipalmitoyl phosphatidic acid in Langmuir monolayers.

Dipalmitoyl phosphatidic acid (DPPA) monolayers at the air-water interface were studied from surface pressure (Pi)-area (A) isotherms and at the microscopic level with Brewster angle microscopy (BAM) under different conditions of temperature, pH, and ionic strength. BAM images were recorded simultaneously with Pi-A isotherms during the monolayer compression-expansion cycles. DPPA monolayers show a structural polymorphism from the liquid-expanded (LE)-liquid-condensed (LC) transition region at lower surface pressures toward liquid-condensed and solid (S) structures at higher surface pressures. An increase in temperature, pH, or ionic strength provokes an expansion in the monolayer structure. The results obtained from the Pi-A measurements are confirmed by the monolayer topography and relative reflectivity. The measurements of relative reflectivity upon monolayer compression showed an increase in relative monolayer thickness of 1.25 and 3.3 times throughout the full monolayer compression from the liquid-expanded to the liquid-condensed and solid states, respectively.

Osmolar Concentration↗
PubMed1997

Phosphatidic acid: a potential signal transducer for cardiac hypertrophy.

Phosphatidic acid (PA) is mainly formed by the hydrolysis of phosphatidylcholine due to the activation of phospholipase D (PLD). PA is also generated by phosphorylation of diacylglycerol (DAG) due to the action of DAG kinase and is converted to DAG under the action of PA phosphohydrolase. Most of the positive inotropic agents which are known to stimulate cardiac hypertrophy, have been shown to increase the level of PA in cardiac sarcolemma. Although the growth factor-like effect of PA has been recognized in a wide variety of tissues, there is a lack of similar information in adult cardiomyocytes. By using single cardiomyocytes, we have now shown that PA increased the basal [Ca2+]i level without significant effect on the amplitude of Ca2+ transients. PA (10-50 mu M) also increased the [Ca2+]i in cardiac cell suspension. PA has also been shown to stimulate protein synthesis in cardiomyocytes, which is inhibited by a PKC inhibitor as well as a Ca2+ chelator. PA at the concentration of 1-50 mu M was observed to stimulate the activity of PLC in cardiac sarcolemma; this effect was attenuated by a PLC inhibitor. Since DAG, formed due to the activation of PLC, is considered to play a crucial role in regulating the activity of protein kinase C (PKC), the positive feedback effect of PA on this pathway may be essential for maintaining the sustained elevation in the activity of PKC during the development of cardiac hypertrophy. In view of these observations and other facts available in the literature, it is suggested that PA may be a potential signal transducer for the development of cardiac hypertrophy.

Animals↗
PubMed1997

The elevation of cellular phosphatidic acid levels caused by polyomavirus transformation can be disassociated from the activation of phospholipase D.

Middle T (mT), the oncogene of murine polyomavirus, causes transformation of rat fibroblasts by activating a number of signal transducing pathways usually used by polypeptide growth factors and their receptors. Here, we report data regarding the activation of signal transducing pathways involving phospholipase D (PL-D). The hydrolysis of phospholipids by PL-D produces phosphatidic acid (PA), a compound with multiple biological effects. The PA content of cells expressing wild-type mT, introduced via a number of different methods, is approximately 50% higher than their untransformed counterparts. This increase in cellular PA content is associated with an approximately 65% increase in PL-D activity in cells expressing wild-type mT. We have also examined the effects of a number of site-directed mutants of mT, on both cellular PA levels and on PL-D activity. Mutants that do not produce mT (Py808A) or that produce a truncated, nonmembrane bound mT (Py1387T) have PA levels similar to that of control cells. Cells expressing the 322YF mutant of mT (which abolishes interaction of mT with phospholipase C gamma1) show increases in both PA levels and PL-D activity that are similar to those seen with wild-type mT. Expression of mutants that abolish the interaction of mT with either shc or with phosphatidylinositol 3-kinase (250YS and 315YF, respectively) cause an increase in PL-D activity comparable to that seen with wild-type mT. However, the PA content of cells expressing these mutants is not elevated. These results suggest that mT causes activation of cellular PL-D, but this activation alone is not sufficient to cause an increase in cellular PA content. Therefore, wild-type mT must affect another, as yet unknown, step in PA metabolism.

Animals↗
PubMed1984

Calcium-dependent atrial slow action potentials generated with phosphatidic acid or phospholipase D.

Phosphatidic acid (PA) formed following phosphatidylinositol hydrolysis has been proposed as a necessary step in receptor-mediated Ca2+ flux. This study demonstrates that PA generates Ca2+-dependent slow action potentials (APs) in rat atrium partially depolarized with 22 mM K+. The slow response was not due to release of endogenous catecholamines or prostaglandin formation since propranolol and indomethacin failed to attenuate the PA-induced slow AP in normal and reserpinized rats. PA-induced slow APs demonstrated Ca2+-dependence such that increasing [Ca2+]o from 0.5 to 5.0 mM caused the amplitude of the slow AP to rise linearly with the logarithm of [Ca2+]o. Phospholipase D (PLD) but not phospholipase C, was able to induce a slow AP, possibly through PA formation. Adenosine attenuated the PA and PLD-induced slow response and aminophylline reversed these effects. The observation that PA and PLD generate Ca2+-dependent slow APs in depolarized rat atrium supports a role for PA mediating Ca2+ influx.

Action Potentials↗
PubMed1986

Adrenergic and cholinergic stimulation of arachidonate and phosphatidate metabolism in cultured astroglial cells.

Primary cultures of neonatal rat brain polygonal astroglia, or cells of the C62B glioma line, were incubated with [1-14C]arachidonic acid (AA) in culture for 18 hr. In both culture systems, more than 80% of the added [1-14C]AA was taken up into cellular glycerolipids; less than 1% of the radioactivity in the cells was present in an unesterified form. When prelabeled C62B cells were stimulated with acetylcholine (ACh), there was a rapid accumulation of arachidonyl-phosphatidic acid (PA) accompanied by a liberation of [1-14C]AA. A variety of other neurotransmitters failed to activate this response in C62B glioma cells. In contrast to the agonist specificity of the response in C62B glioma cells, primary astroglia generated PA and liberated [1-14C]AA in response to several neurotransmitters (i.e., ACh, norepinephrine, glutamate, and histamine) Treatment of astroglia with a combination of norepinephrine, ACh, and histamine resulted in a greater production of PA and free [1-14C]AA than did treatment with any one of these neurotransmitters alone. The results suggest that cultures of astroglia can respond to several different neurotransmitters with specific changes in AA and PA metabolism. Thus, a variety of neurotransmitters initiate cascades of lipid metabolism which may be of physiological significance in glial function.

Animals↗
PubMed1996

Dietary sunflower oil reduces plasma and liver triacylglycerols in fasting rats and is associated with decreased liver microsomal phosphatidate phosphohydrolase activity.

Plasma and liver lipids were studied in male weanling rats fed diets containing moderate levels of fat (6% by weight) as sunflower oil (SF diet, rich in linoleic acid), salmon oil (SM diet, rich in long-chain n-3 fatty acids), or a blend of peanut and rapeseed oil (PR diet, rich in oleic acid). After nine weeks of feeding, the fasting plasma cholesterol concentrations were 49 and 24% lower in groups SM and SF, respectively, as compared to group PR. Both dietary salmon oil and sunflower oil lowered the triacylglycerol concentration of plasma and liver but, unexpectedly, the response was higher with sunflower oil. Indeed, in group SM the values were 15 and 30% lower in plasma and liver, whereas in group SF, they were 24 and 53% lower, respectively. As compared to group PR, liver triacylglycerols and microsomes contained 2.5- and 2.3-fold less oleic acid, respectively, in group SF, and they were 9.2- and 3.2-fold enriched in n-3 fatty acids, respectively, in group SM. The liver triacylglycerol concentrations were correlated with changes in the microsomal Mg(2+)-dependent phosphatidate phosphohydrolase activity (r = 0.47, P < 0.01). As oleic acid, unlike long-chain n-3 fatty acids, is considered to promote the triacylglycerol synthesis and secretion, our findings suggest that changes in the membrane fatty acid composition could affect the triacylglycerol content of liver and plasma. Moreover, the availability within the liver, of oleic acid, predominantly incorporated into triacylglycerols, might limit the triacylglycerol production in SF-fed rats.

Animals↗
PubMed1980

Distribution of the phosphatidate phosphohydrolase activity in the lamellar body and lysosomal fractions of lung tissue.

Phosphatidate phosphohydrolase (PAPase) activity was measured in lamellar bodies purified from porcine lung tissue. After repeated freeze-thawing, only a negligible amount of PAPase activity was released into the soluble fractions, whereas there was release of 2 lysosomal marker enzyme activities, glucosaminidase and beta-galactosidase into the soluble fraction. In addition, a lysosomal-enriched fraction was prepared from adult rat lung tissue by prior treatment of the rats with Triton WR 1339. Treatment with Triton WR 1339 resulted in the significant shift of the activities of the lysosomal marker enzymes, glucosaminidase and beta-galactosidase, to less dense subcellular fractions. The highest specific activity of PAPase was found in a subcellular fraction which had a density that was intermediate between that of the mitochondrial and microsomal fractions and the distribution of PAPase activity was not affected by the prior treatment of the rats with Triton WR 1339.

Animals↗
PubMed1988

Modulation of calcium phosphate formation by phosphatidate-containing anionic liposomes.

Liposome prepared from 7:2:1 molar mixtures of phosphatidylcholine, dicetyl phosphate, and cholesterol to which 1-20 mole % dioleoylphosphatidic acid (DOPA) was added were used to examine the effect of membrane-bound monoester phosphatidate anions on calcium phosphate formation in aqueous solutions at 22 degrees C, pH 7.4 and 240 mOsm. Results showed that up to 20 mole % DOPA in the liposomal envelope did not initiate mineralization in solutions made metastable with 2.25 mM CaCl2 and 1.50 mM KH2PO4. Results alos revealed that precipitation induced in metastable solutions by the seeding action of intraliposomally formed mineral was measurably reduced with as little as 1 mole % DOPA and completely suppressed with 5 mole % DOPA. In contrast, 10 mole % concentrations of diester phosphate lipids either had no effect on extraliposomal precipitation (e.g., phosphatidylglycerol and phosphatidylinositol) or, as reported previously for phosphatidylserine) only partially reduced the amount of precipitate formed. Transmission electron microscopical analysis suggests that DOPA-containing lipid bilayers adhering to the seed crystals inhibited extraliposomal mineralization by encapsulating the crystals within the liposomes and/or by blocking potential growth sites on the crystal faces. The polar head group of DOPA, being more negatively charged and sterically less encumbered than diester phosphate ligands, most probably was responsible for this adherence of the lipid bilayers to the crystal surfaces.

Animals↗
PubMed1998

Regulation of PDE-4 cAMP phosphodiesterases by phosphatidic acid.

Phosphatidic acid (PA) has been previously shown to activate specifically some of the isoforms of type 4 cylic nucleotide phosphodiesterases (PDE-4) in an acellular system. In the present work, we have investigated the mechanism of PA-activating effect by using a recombinant PA-sensitive isoform, PDE-4D3. The enzyme was specifically activated by acidic phospholipids, but not by zwitterionic phospholipids or anionic detergents. The importance of the role of PA acidic groups in the activation process was confirmed by studying the influence of pH and ionic strength on activation. Crosslinking experiments suggested that PA might influence the ability of PDE-4D3 to form dimers. Binding studies performed with radiolabeled PA showed that PA binds to a PDE-4D3 preparation in a saturable manner. Specifically bound PA was displaced by anionic, but not by zwitterionic phospholipids. With a preparation of PDE-4B2, a PDE-4 isoform insensitive to PA activation, PA binding was only displaced by high concentrations of unlabeled PA, suggesting that high-affinity PA binding sites are only present on PDE-4D3. These data support the hypothesis that PA-activating effect depends on direct binding of the effector on specific sites carried by the PDE-4D3 protein.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Phosphatidic acid produced by phospholipase D is required for tobacco pollen tube growth.

Phospholipase D (PLD) and its product phosphatidic acid (PA) are involved in a number of signalling pathways regulating cell proliferation, membrane vesicle trafficking and defence responses in eukaryotic cells. Here we report that PLD and PA have a role in the process of polarised plant cell expansion as represented by pollen tube growth. Both phosphatidylinositol-4,5-bisphosphate-dependent and independent PLD activities were identified in pollen tube extracts, and activity levels during pollen tube germination and growth were measured. PLD-mediated PA production in vivo can be blocked by primary alcohols, which serve as a substrate for the transphosphatidylation reaction. Both pollen germination and tube growth are stopped in the presence 0.5% 1-butanol, whereas secondary and tertiary isomers do not show any effect. This inhibition could be overcome by addition of exogenous PA-containing liposomes. In the absence of n-butanol, addition of a micromolar concentration of PA specifically stimulates pollen germination and tube elongation. Furthermore, a recently established link between PLD and microtubule dynamics was supported by taxol-mediated partial rescue of the 1-butanol-inhibited pollen tubes. The potential signalling role for PLD-derived PA in plant cell expansion is discussed.

1-Butanol↗
PubMed2005

Polyamines are essential for the synthesis of 2-ricinoleoyl phosphatidic acid in developing seeds of castor.

The major fatty acid component of castor (Ricinus communis L.) oil is ricinoleic acid (12-hydroxy-cis-9-octadecenoic acid), and unsaturated hydroxy acid accounts for >85% of the total fatty acids in triacylglycerol (TAG). TAG had a higher ricinoleate content at position 2 than at positions 1 and 3. Although lysophosphatidic acid (LPA) acyltransferase (EC 2.3.1.51), which catalyzes acylation of LPA at position 2, was expected to utilize ricinoleoyl-CoA preferentially over other fatty acyl-CoAs, no activity was found for ricinoleoyl-CoA in vitro at concentrations at which other unsaturated acyl-CoAs were incorporated rapidly. However, activity for ricinoleoyl-CoA appeared with addition of polyamines (putrescine, spermidine, and spermine), while polyamines decreased the rates of incorporation of other acyl-CoAs into position 2. The order of effect of polyamines on LPA acyltransferase activity was spermine > spermidine >> putrescine. At concentrations of spermine and spermidine of >0.1 mM, ricinoleoyl-CoA served as an effective substrate for LPA acyltransferase reaction. The concentrations of spermine and spermidine in the developing seeds were estimated at approximately 0.09 and approximately 0.63 mM, respectively. These stimulatory effects for incorporation of ricinoleate were specific to polyamines, but basic amino acids were ineffective as cations. In contrast, in microsomes from safflower seeds that do not contain ricinoleic acid, spermine and spermidine stimulated the LPA acyltransferase reaction for all acyl-CoAs tested, including ricinoleoyl-CoA. Although the fatty acid composition of TAG depends on both acyl-CoA composition in the cell and substrate specificity of acyltransferases, castor bean polyamines are crucial for incorporation of ricinoleate into position 2 of LPA. Polyamines are essential for synthesis of 2-ricinoleoyl phosphatidic acid in developing castor seeds.

Acetyl Coenzyme A↗
PubMed2006

Aluminum inhibits phosphatidic acid formation by blocking the phospholipase C pathway.

Aluminum (Al(3+)) has been recognized as a main toxic factor in crop production in acid lands. Phosphatidic acid (PA) is emerging as an important lipid signaling molecule and has been implicated in various stress-signaling pathways in plants. In this paper, we focus on how PA generation is affected by Al(3+) using Coffea arabica suspension cells. We pre-labeled cells with [(32)P]orthophosphate ((32)Pi) and assayed for (32)P-PA formation in response to Al(3+). Treating cells for 15 min with either AlCl(3) or Al(NO(3))(3) inhibited the formation of PA. In order to test how Al(3+) affected PA signaling, we used the peptide mastoparan-7 (mas-7), which is known as a very potent stimulator of PA formation. The Al(3+) inhibited mas-7 induction of PA response, both before and after Al(3+) incubation. The PA involved in signaling is generated by two distinct phospholipid signaling pathways, via phospholipase D (PLD; EC: 3.1.4.4) or via Phospholipase C (PLC; EC: 3.1.4.3), and diacylglycerol kinase (DGK; EC 2.7.1.107). By labeling with (32)Pi for short periods of time, we found that PA formation was inhibited almost 30% when the cells were incubated with AlCl(3) suggesting the involvement of the PLC/DGK pathway. Incubation of cells with PLC inhibitor, U73122, affected PA formation, like AlCl(3) did. PLD in vivo activation by mas-7 was reduced by Al(3+). These results suggest that PA formation was prevented through the inhibition of the PLC activity, and it provides the first evidence for the role of Al toxicity on PA production.

Aluminum Chloride↗
PubMed2005

Cloning and characterization of a novel human phosphatidic acid phosphatase type 2, PAP2d, with two different transcripts PAP2d_v1 and PAP2d_v2.

This study reports the cloning and characterization of a novel human phosphatidic acid phosphatase type 2 isoform cDNAs (PAP2d) from the foetal brain cDNA library. The PAP2d gene is localized on chromosome 1p21.3. It contains six exons and spans 112 kb of the genomic DNA. By large-scale cDNA sequencing we found two splice variants of PAP2d, PAP2d_v1 and PAP2d_v2. The PAP2d_v1 cDNA is 1722 bp in length and spans an open reading frame from nucleotide 56 to 1021, encoding a 321aa protein. The PAP2d_v2 cDNA is 1707 bp in length encoding a 316aa protein from nucleotide 56-1006. The PAP2d_v1 cDNA is 15 bp longer than the PAP2d_v2 cDNA in the terminal of the fifth exon and it creates different ORF. Both of the proteins contain a well-conserved PAP2 motif. The PAP2d_v1 is mainly expressed in human brain, lung, kidney, testis and colon, while PAP2d_v2 is restricted to human placenta, skeletal muscle, and kidney. The two splice variants are co-expressed only in kidney.

Alternative Splicing↗
PubMed1990

Determination of platelet adhesion to collagen and the associated formation of phosphatidic acid and calcium mobilization.

A method was developed to study the adhesion of platelets to fibrillar collagen at 37 degrees C in the absence of aggregation. Human platelets were labeled with [3H]-oleic acid, gel-filtered, and incubated with collagen in the presence of receptor antagonists to thromboxane A2, 5-hydroxytryptamine, and platelet-activating factor, as well as a fibrinogen/fibronectin inhibitor and an ADP-removing system. Those platelets that adhered to collagen were separated from those that did not by filtration through a 10-microns nylon mesh and the extent of platelet adhesion was quantitated by determination of the radioactivity retained by the mesh. The extent of platelet adhesion was proportional to the amount of collagen added up to 100 micrograms/ml and was essentially complete by 1 min. At least 80-90% of the platelets were capable of adhering to collagen. Adhesion was potentiated by the presence of extracellular Mg2+ and this potentiation was inhibited by extracellular Ca2+. Phosphatidic acid increased markedly in those platelets that adhered to collagen and this was associated with increases in cytosolic free Ca2+ levels that could be detected using the fluorescent Ca2+ indicator fura-2.

Blood Platelets↗
PubMed1984

Enhanced de novo synthesis of phosphatidic acid and phosphatidylinositol in rat pancreatic islets exposed to nutrient or neurotransmitter stimuli.

A stimulation of [3H]glycerol incorporation into phosphatidic acid and phosphatidylinositol was observed upon exposure of rat pancreatic islets to the nutrient secretagogues alpha-ketoisocaproate and glucose, or to the neurotransmitter stimuli carbamylcholine and cholecystokinin. These effects were associated with reduced labeling of phosphatidylcholine and, in some cases, phosphatidylethanolamine. The modified patterns of [3H]glycerol incorporation into islet phospholipids persisted in the absence of added Ca2+, but were abolished by excess EDTA. Nutrient, but not neurotransmitter, secretagogues also stimulated the incorporation of [3H]glycerol into triacylglycerols. The results suggest that the stimulation of islets with the above classes of secretagogues is accompanied by enhanced de novo synthesis of acidic phospholipids.

Animals↗
PubMed1984

Phosphatidic acid and the calcium-dependent actions of gonadotropin-releasing hormone in pituitary gonadotrophs.

The stimulation of luteinizing hormone (LH) release and cyclic GMP (cGMP) production in rat anterior pituitary cells by gonadotropin-releasing hormone (GnRH) are receptor mediated and calcium dependent, and have been shown to be accompanied by increased phospholipid turnover and arachidonic acid release. The incorporation of 32Pi into the total phospholipid fraction of pituitary gonadotrophs was significantly elevated by 10(-8) M GnRH, with specific increases in the labeling of phosphatidylinositol and phosphatidic acid (PA). Since PA acts as a calcium ionophore in several cell types, its effects upon calcium-mediated gonadotroph responses were compared with those elicited by GnRH. In rat pituitary gonadotrophs prepared by centrifugal elutriation, PA stimulated LH release and cGMP production by 9-fold and 5-fold, respectively. The stimulation of LH release by 30 microM PA was biphasic in its dependence on extracellular calcium concentration, rising from zero in the absence of calcium to a maximum of 10-fold at 0.5 mM Ca2+ and declining at higher calcium concentrations. In dose-response experiments, PA was 3-fold more potent at 0.5 mM Ca2+ than at 1.2 mM Ca2+. The cGMP response to PA in cultured gonadotrophs was also calcium dependent, and was progressively enhanced by increasing Ca2+ concentrations up to 1.5 mM. The ability of PA to stimulate both LH release and cGMP formation in a calcium-dependent manner suggests that endogenous PA formed in response to GnRH receptor activation could function as a Ca2+ ionophore in pituitary gonadotrophs, and may participate in the stimulation of gonadotroph responses by GnRH and its agonist analogs.

Animals↗
PubMed1984

Acetylglyceryl ether phosphorylcholine (AGEPC; platelet-activating factor)-induced stimulation of rabbit platelets: correlation between phosphatidic acid level, 45Ca2+ uptake, and [3H]serotonin secretion.

When 32Pi-labeled rabbit platelets were incubated with 5 X 10(-10) M 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC), either in the presence or absence (0.1 mM EGTA) of added Ca2+, there was a three- to five-fold increase in the [32P]phosphatidic acid (PA) pool within 15 to 20 s. This event was followed by a gradual decrease in the [32P]PA level to near basal level in 5 min. AGEPC effected this change in [32P]PA in a characteristic dose- and time-dependent manner. Polar head group analogs of AGEPC, such as AGEDME and AGEMME, also effected an increase in PA labeling at levels comparable to those previously reported for their activity toward rabbit platelets [K. Satouchi, R. N. Pinckard, L. M., McManus, and D. J. Hanahan (1981) J. Biol. Chem. 256, 4425-4432]. Other analogs, i.e., lysoGEPC and the enantiomer, sn-1-AGEPC, which are inactive toward rabbit platelets, also showed no effect on the level of [32P]PA. The finding that the PA level in rabbit platelets could be manipulated by the addition of AGEPC, without any added Ca2+, provided an excellent model system for establishing a correlation between the uptake of Ca2+, serotonin release, and PA level. Thus, PA must be regarded as a sensitive indicator of a reaction mechanism important to the platelet response to AGEPC, and could be the focal point in promoting calcium uptake during the stimulation process.

Animals↗
PubMed1980

Ion specificity in fusion of phosphatidic acid-phosphatidylcholine mixed lipid vesicles.

Fusion of phosphatidylcholine-phosphatidic acid mixed lipid vesicles has been studied under the influence of the divalent Ca2+, Mg2+, Cd2+, and Ba2+, which range in size from much smaller to much larger, than Ca2+. Fusion has also been studied under the influence of Eu3+, which has a similar radius but different charge. The effects of these ions are reflected in the different degrees of fusion determined by changes in vesicle size, and in the varying fusion rates monitored by 1H-NMR spectroscopy. Cd2+, which has an ionic radius similar to Ca2+, exhibits the same effect on fusion as Ca2+, while other ions show lower efficiencies. This suggests that the vesicle fusion intermediate has a geometry ideally suited to the binding of Ca2+ or Cd2+.

Barium↗