Academic literature on the topic 'Phosphatidic acid (PA)'
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Journal articles on the topic "Phosphatidic acid (PA)"
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Sakane, Fumio, Fumi Hoshino, and Chiaki Murakami. "New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein." International Journal of Molecular Sciences 21, no. 18 (September 16, 2020): 6794. http://dx.doi.org/10.3390/ijms21186794.
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Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Mammalian DGK consists of ten isozymes (α–κ) and governs a wide range of physiological and pathological events, including immune responses, neuronal networking, bipolar disorder, obsessive-compulsive disorder, fragile X syndrome, cancer, and type 2 diabetes. DG and PA comprise diverse molecular species that have different acyl chains at the sn-1 and sn-2 positions. Because the DGK activity is essential for phosphatidylinositol turnover, which exclusively produces 1-stearoyl-2-arachidonoyl-DG, it has been generally thought that all DGK isozymes utilize the DG species derived from the turnover. However, it was recently revealed that DGK isozymes, except for DGKε, phosphorylate diverse DG species, which are not derived from phosphatidylinositol turnover. In addition, various PA-binding proteins (PABPs), which have different selectivities for PA species, were recently found. These results suggest that DGK–PA–PABP axes can potentially construct a large and complex signaling network and play physiologically and pathologically important roles in addition to DGK-dependent attenuation of DG–DG-binding protein axes. For example, 1-stearoyl-2-docosahexaenoyl-PA produced by DGKδ interacts with and activates Praja-1, the E3 ubiquitin ligase acting on the serotonin transporter, which is a target of drugs for obsessive-compulsive and major depressive disorders, in the brain. This article reviews recent research progress on PA species produced by DGK isozymes, the selective binding of PABPs to PA species and a phosphatidylinositol turnover-independent DG supply pathway.
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Zegarlinska, Jolanta, Magda Piaścik, Aleksander F. Sikorski, and Aleksander Czogalla. "Phosphatidic acid – a simple phospholipid with multiple faces." Acta Biochimica Polonica 65, no. 2 (July 8, 2018): 163–71. http://dx.doi.org/10.18388/abp.2018_2592.
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Phosphatidic acid (PA) is the simplest glycerophospholipid naturally occurring in living organisms, and even though its content among other cellular lipids is minor, it is drawing more and more attention due to its multiple biological functions. PA is a precursor for other phospholipids, acts as a lipid second messenger and, due to its structural properties, is also a modulator of membrane shape. Although much is known about interaction of PA with its effectors, the molecular mechanisms remain unresolved to a large degree. Throughout many of the well-characterized PA cellular sensors, no conserved binding domain can be recognized. Moreover, not much is known about the cellular dynamics of PA and how it is distributed among subcellular compartments. Remarkably, PA can play distinct roles within each of these compartments. For example, in the nucleus it behaves as a mitogen, influencing gene expression regulation, and in the Golgi membrane it plays a role in membrane trafficking. Here we discuss how a biophysical experimental approach enabled PA behavior to be described in the context of a lipid bilayer and to what extent various physicochemical conditions may modulate the functional properties of the lipid. Understanding these aspects would help to unravel specific mechanisms of PA-driven membrane transformation and protein recruitment and thus would lead to a clearer picture of the biological role of PA.
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Huang, Shanjin, Lisa Gao, Laurent Blanchoin, and Christopher J. Staiger. "Heterodimeric Capping Protein fromArabidopsisIs Regulated by Phosphatidic Acid." Molecular Biology of the Cell 17, no. 4 (April 2006): 1946–58. http://dx.doi.org/10.1091/mbc.e05-09-0840.
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The cytoskeleton is a key regulator of morphogenesis, sexual reproduction, and cellular responses to extracellular stimuli. Changes in the cellular architecture are often assumed to require actin-binding proteins as stimulus-response modulators, because many of these proteins are regulated directly by binding to intracellular second messengers or signaling phospholipids. Phosphatidic acid (PA) is gaining widespread acceptance as a major, abundant phospholipid in plants that is required for pollen tube tip growth and mediates responses to osmotic stress, wounding, and phytohormones; however, the number of identified effectors of PA is rather limited. Here we demonstrate that exogenous PA application leads to significant increases in filamentous actin levels in Arabidopsis suspension cells and poppy pollen grains. To investigate further these lipid-induced changes in polymer levels, we analyzed the properties of a key regulator of actin filament polymerization, the heterodimeric capping protein from Arabidopsis thaliana (AtCP). AtCP binds to PA with a Kdvalue of 17 μM and stoichiometry of ∼1:2. It also binds well to PtdIns(4,5)P2, but not to several other phosphoinositide or acidic phospholipids. The interaction with PA inhibited the actin-binding activity of CP. In the presence of PA, CP is unable to block the barbed or rapidly growing and shrinking end of actin filaments. Precapped filament barbed ends can also be uncapped by addition of PA, allowing rapid filament assembly from an actin monomer pool that is buffered with profilin. The findings support a model in which the inhibition of CP activity in cells by elevated PA results in the stimulation of actin polymerization from a large pool of profilin-actin. Such regulation may be important for the response of plant cells to extracellular stimuli as well as for the normal process of pollen tube tip growth.
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Baba, Takashi, Yuriko Kashiwagi, Nagisa Arimitsu, Takeshi Kogure, Ayumi Edo, Tomohiro Maruyama, Kazuki Nakao, et al. "Phosphatidic Acid (PA)-preferring Phospholipase A1Regulates Mitochondrial Dynamics." Journal of Biological Chemistry 289, no. 16 (March 5, 2014): 11497–511. http://dx.doi.org/10.1074/jbc.m113.531921.
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Henry, R. A., S. Y. Boyce, T. Kurz, and R. A. Wolf. "Stimulation and binding of myocardial phospholipase C by phosphatidic acid." American Journal of Physiology-Cell Physiology 269, no. 2 (August 1, 1995): C349—C358. http://dx.doi.org/10.1152/ajpcell.1995.269.2.c349.
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Exposure of adult ventricular myocytes to exogenous natural phosphatidic acid results in the production of inositol phosphates by unknown mechanism(s). We characterized stimulation of myocytic phosphoinositide-specific phospholipase C (PLC) by synthetic dioleoyl phosphatidic acid (PA) as a potential mechanism for modulation of inositol phosphate production. Our data demonstrate that exogenous PA, at 10(-8)-10(-5) M, caused a concentration-dependent increase in inositol 1,4,5-trisphosphate in adult rabbit ventricular myocytes. PA also caused a concentration-dependent increase in in vitro activity of myocytic PLC in the presence or absence of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). PLC-delta 1, the predominant isozyme of PLC expressed in adult rabbit ventricular myocytes, bound to liposomes of PA with high affinity in the presence of EGTA. The phosphomonoester group of PA was critical to in vitro stimulation of myocytic PLC activity and high-affinity binding of PLC-delta 1. We propose that binding of PLC-delta 1 to phosphatidic acid may be a novel mechanism for dynamic membrane association and modulation of PLC in adult ventricular myocytes.
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Ganesan, Suriakarthiga, Brittney N. Shabits, and Vanina Zaremberg. "Tracking Diacylglycerol and Phosphatidic Acid Pools in Budding Yeast." Lipid Insights 8s1 (January 2015): LPI.S31781. http://dx.doi.org/10.4137/lpi.s31781.
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Phosphatidic acid (PA) and diacylglycerol (DAG) are key signaling molecules and important precursors for the biosynthesis of all glycerolipids found in eukaryotes. Research conducted in the model organism Saccharomyces cerevisiae has been at the forefront of the identification of the enzymes involved in the metabolism and transport of PA and DAG. Both these lipids can alter the local physical properties of membranes by introducing negative curvature, but the anionic nature of the phosphomonoester headgroup in PA sets it apart from DAG. As a result, the mechanisms underlying PA and DAG interaction with other lipids and proteins are notoriously different. This is apparent from the analysis of the protein domains responsible for recognition and binding to each of these lipids. We review the current evidence obtained using the PA-binding proteins and domains fused to fluorescent proteins for in vivo tracking of PA pools in yeast. In addition, we present original results for visualization of DAG pools in yeast using the C1 domain from mammalian PKCδ. An emerging first cellular map of the distribution of PA and DAG pools in actively growing yeast is discussed.
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Noh, Ji-Yoon, Kyung-Min Lim, Ok-Nam Bae, Seung-Min Chung, Sang-Wook Lee, Kyung-Mi Joo, Sin-Doo Lee, and Jin-Ho Chung. "Procoagulant and prothrombotic activation of human erythrocytes by phosphatidic acid." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 2 (August 2010): H347—H355. http://dx.doi.org/10.1152/ajpheart.01144.2009.
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Increased phosphatidic acid (PA) and phospholipase D (PLD) activity are frequently observed in various disease states including cancers, diabetes, sepsis, and thrombosis. Previously, PA has been regarded as just a precursor for lysophosphatidic acid (LPA) and diacylglycerol (DAG). However, increasing evidence has suggested independent biological activities of PA itself. In the present study, we demonstrated that PA can enhance thrombogenic activities in human erythrocytes through phosphatidylserine (PS) exposure in a Ca2+-dependent manner. In freshly isolated human erythrocytes, treatment of PA or PLD induced PS exposure. PA-induced PS exposure was not attenuated by inhibitors of phospholipase A2or phosphatidate phosphatase, which converts PA to LPA or DAG. An intracellular Ca2+increase and the resultant activation of Ca2+-dependent PKC-α appeared to underlie the PA-induced PS exposure through the activation of scramblase. A marginal decrease in flippase activity was also noted, contributing further to the maintenance of exposed PS on the outer membrane. PA-treated erythrocytes showed strong thrombogenic activities, as demonstrated by increased thrombin generation, endothelial cell adhesion, and erythrocyte aggregation. Importantly, these procoagulant activations by PA were confirmed in a rat in vivo venous thrombosis model, where PA significantly enhanced thrombus formation. In conclusion, these results suggest that PA can induce thrombogenic activities in erythrocytes through PS exposure, which can increase thrombus formation and ultimately contribute to the development of cardiovascular diseases.
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Nanjundan, Meera, and Fred Possmayer. "Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 1 (January 1, 2003): L1—L23. http://dx.doi.org/10.1152/ajplung.00029.2002.
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The lung contains two distinct forms of phosphatidic acid phosphatase (PAP). PAP1 is a cytosolic enzyme that is activated through fatty acid-induced translocation to the endoplasmic reticulum, where it converts phosphatidic acid (PA) to diacylglycerol (DAG) for the biosynthesis of phospholipids and neutral lipids. PAP1 is Mg2+ dependent and sulfhydryl reagent sensitive. PAP2 is a six-transmembrane-domain integral protein localized to the plasma membrane. Because PAP2 degrades sphingosine-1-phosphate (S1P) and ceramide-1-phosphate in addition to PA and lyso-PA, it has been renamed lipid phosphate phosphohydrolase (LPP). LPP is Mg2+independent and sulfhydryl reagent insensitive. This review describes LPP isoforms found in the lung and their location in signaling platforms (rafts/caveolae). Pulmonary LPPs likely function in the phospholipase D pathway, thereby controlling surfactant secretion. Through lowering the levels of lyso-PA and S1P, which serve as agonists for endothelial differentiation gene receptors, LPPs regulate cell division, differentiation, apoptosis, and mobility. LPP activity could also influence transdifferentiation of alveolar type II to type I cells. It is considered likely that these lipid phosphohydrolases have critical roles in lung morphogenesis and in acute lung injury and repair.
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Kim, Sang-Chul, and Xuemin Wang. "Phosphatidic acid: an emerging versatile class of cellular mediators." Essays in Biochemistry 64, no. 3 (July 9, 2020): 533–46. http://dx.doi.org/10.1042/ebc20190089.
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Abstract Lipids function not only as the major structural components of cell membranes, but also as molecular messengers that transduce signals to trigger downstream signaling events in the cell. Phosphatidic acid (PA), the simplest and a minor class of glycerophospholipids, is a key intermediate for the synthesis of membrane and storage lipids, and also plays important roles in mediating diverse cellular and physiological processes in eukaryotes ranging from microbes to mammals and higher plants. PA comprises different molecular species that can act differently, and is found in virtually all organisms, tissues, and organellar membranes, with variations in total content and molecular species composition. The cellular levels of PA are highly dynamic in response to stimuli and multiple enzymatic reactions can mediate its production and degradation. Moreover, its unique physicochemical properties compared with other glycerophospholipids allow PA to influence membrane structure and dynamics, and interact with various proteins. PA has emerged as a class of new lipid mediators modulating various signaling and cellular processes via its versatile effects, such as membrane tethering, conformational changes, and enzymatic activities of target proteins, and vesicular trafficking.
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Antonescu, Costin N., Gaudenz Danuser, and Sandra L. Schmid. "Phosphatidic Acid Plays a Regulatory Role in Clathrin-mediated Endocytosis." Molecular Biology of the Cell 21, no. 16 (August 15, 2010): 2944–52. http://dx.doi.org/10.1091/mbc.e10-05-0421.
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Clathrin-mediated endocytosis (CME) is the main route of internalization of receptor-ligand complexes. Relatively little is known about the role of specific lipids in CME, in particular that of phosphatidic acid (PA). We examined the effect of altering cellular PA levels on CME by manipulating the activities and/or levels of either phospholipase D (PLD1 and PLD2) or diacylglycerol kinase (DGK), two enzyme classes involved in PA production. DGK inhibition resulted in a dramatic reduction of cellular PA, measured directly using an enzyme-coupled reaction, which resulted in a decreased rate of EGFR internalization measured biochemically. This corresponded to a decreased rate of clathrin-coated pit (CCP) initiation and increased lifetimes of productive CCPs, as determined by quantitative live-cell total internal reflection fluorescence microscopy. Unexpectedly, PLD inhibition caused an increase in cellular PA, suggesting that PLD activity negatively regulates PA synthesis by other more productive pathways. Consistent with opposite effects on cellular PA levels, PLD inhibition had opposite effects on EGFR internalization and CCP dynamics, compared with DGK inhibition. Importantly, the constitutive internalization of transferrin receptors was unaffected by either treatment. These findings demonstrate that PA plays a regulatory rather than obligatory role in CME and differentially regulates ligand-stimulated CME of EGFR.
Dissertations / Theses on the topic "Phosphatidic acid (PA)"
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Williams, David. "Phosphatidic Acid Increases Lean Body Tissue and Strength In Resistance Trained Men." Master's thesis, University of Central Florida, 2012. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5575.
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Phosphatidic Acid (PA) is a natural phospholipid compound derived from lecithin which is commonly found in egg yolk, grains, fish, soybeans, peanuts and yeast. It has been suggested that PA is involved in several intracellular processes associated with muscle hypertrophy. Specifically, PA has been reported to activate protein synthesis through the mammalian target of rapamycin (mTOR) signaling pathway and thereby may enhance the anabolic effects of resistance training. To our knowledge, no one has examined the effect of PA supplementation in humans while undergoing a progressive resistance training program. To examine the effect of PA supplementation on lean soft tissue mass (LM) and strength after 8 weeks of resistance training. Fourteen resistance-trained men (mean [plus or minus] SD; age 22.7 [plus or minus] 3.3 yrs; height: 1.78 [plus or minus] 0.10m; weight: 89.3 [plus or minus] 16.3 kg) volunteered to participate in this randomized, double-blind, placebo-controlled, repeated measures study. The participants were assigned to a PA group (750mg/day; Mediator, ChemiNutra, MN, n=7) or placebo group (PL; rice flower; n=7), delivered in capsule form that was identical in size, shape and color. Participants were tested for 1RM strength in the bench press (BP) and squat (SQ) exercise. LM was measured using dual-energy X-ray absorptiometry. After base line testing, the participants began supplementing PA or PL for 8 weeks during a progressive resistance training program intended for muscular hypertrophy. Data was analyzed using magnitude-based inferences on mean changes for BP, SQ and LM. Furthermore, the magnitudes of the inter-relationships between changes in total training volume and LM were interpreted using Pearson correlation coefficients, which had uncertainty (90% confidence limits) of approximately +0.25. In the PA group, the relationship between changes in training volume and LM was large (r=0.69, [plus or minus] 0.27; 90%CL), however, in the PL group the relationship was small (r=0.21, [plus or minus] 0.44; 90%CL). PA supplementation was determined to be likely beneficial at improving SQ and LM over PL by 26% and 64%, respectively. The strong relationship between changes in total training volume and LM in the PA group suggest that greater training volume most likely lead to the greater changes in LM, however, no such relationship was found with PL group. For the BP data, the PA group resulted in a 42% greater increase in strength over PL, although the effect was considered unclear. While more research is needed to elucidate mechanism of action; the current findings suggest that in experienced resistance trained men supplementing 750mg PA per day for 8 weeks may likely benefit greater changes in muscle mass and strength compared with resistance training only.M.S.
Masters
Child, Family and Community Sciences
Education and Human Performance
Sport and Exercise Sciences; Applied Exercise Physiology
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Szabová, Jana. "Příprava a charakterizace komplexních liposomálních systémů pro distribuci léčiv." Master's thesis, Vysoké učení technické v Brně. Fakulta chemická, 2019. http://www.nusl.cz/ntk/nusl-401880.
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This diploma thesis deals with the preparation and characterization of stealth liposomes and their combination with trimethylchitosan (TMC). This complex could find application in the field of inhalation administration. Stealth liposomes were prepared from neutral phophatidylcholine, negatively charged fosfatidic acid and polyethyleneglycol bounded to phosphatidylethanolamine. We have managed to prepare stealth liposomes with suitable properties that should guarantee passive targeting without evocation an immune response, despite the content of the negative component. We also found a suitable method of preparation for stealth liposome–TMC complex, where the change of size and zeta potential confirmed the non–covalent bound between two components despite the content of the polyethyleneglycol.
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Repová, Romana. "Studium interakce záporně nabitých vezikulárních systémů s polykationty." Master's thesis, Vysoké učení technické v Brně. Fakulta chemická, 2020. http://www.nusl.cz/ntk/nusl-414178.
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This diploma thesis deals with the preparation and characterization of negatively charged catanionic vesicular systems and their combination with selected polycations. The catanionic vesicular system was prepared by mixing of two oppositely charged surfactants SDS and CTAB. The negative charge as well as the stability of the vesicular system was provided by the incorporation of phosphatidic acid. Polycations, DEAE and TMC, have been selected for use in a pharmaceutical applications. Characterization of the prepared systems was performed by measuring DLS and ELS. The results indicate that we were able to prepare stable negatively charged vesicles that were eligible to non-covalently interact with selected polycations.
Conference papers on the topic "Phosphatidic acid (PA)"
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Tysnes, O.-B., AJ M. Verhoeven, and H. Holmsen. "Thrombin stimulation of human platelets:Phosphoinositides as the only source of the diacylglycerol moiety in phosphatidic acid." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644505.
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Recent reports on various cell types including platelets have concluded in the heterogenous production of phosphatidic acid (PA) during the stimulus-response coupling. Human platelets were pulse-labelled simultaneously with [32P] P. and [32H]glycerol. Extracts were analyzed for masses and radioactivities of ATP and phosphoinositides. When the cells were stimulated with low concentrations of thrombin, the production of [32P] PA was evident without measurable production of [3H] PA. At higher doses of the agonist,[3H] PA was formed, but distinctly later than [32P] PA.This suggested a heterogenous production of PA upon thrombin stimulation of platelets. The specific H-radioactivity of PA in unstimulated cells was about 50% of that of the phosphoinositides. Upon l80 sec of stimulation with 0.5 U/ml of thrombin, the specific [3H] PA radioactivity increased to the level of the phosphoinositides which remained constant during platelet activation. Since other phospholipids incorporate [3H] glycerol much slower than the phosphoinositides, these latter remain the only possible source of the diacylglycerol moiety of PA. The specific 32P-radioactivity of PA in unstimulated cells was only 4% of that of α-ATP and similar to the specific 32P-radioactivity of phosphatidylinositol in unstimulated platelets. After Jyijin of stimulation with 0.5 U/ml of thrombin, specific [32P] PA was similar to that of γ-ATP. The descrepancy in [32P] Pi. and [3H] glycerol incorporation into PA upon thrombin stimulation of platelets is therefore mainly due to a thrombin-induced shift inspecific 32P-radioactivity in PA.
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Cascar, J. M., and J. L. Kavarro. "ARACHIDGIIC ACID METABOLISM II PLATELETS STORED FOR FIVE DAYS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644685.
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Arachidonlc acid (AA) netabolisn has been extensively studied in fresh platelets, but there Is little infomation available for stored platelets . we stored platelets in CLI bags far five days at 22+/-2°C and, on days 0, 3 and 5, six si of platelet concentrate were revved from the container and platelets were labeled with (C-14J-AA. Both incorporation and distribution of radiotracer sere studied in rest and thrcnfcln stivlated platelets.Total uptake of, (C-14)-AA dropped fron day 0 to 5 (p 0.01). Distribution oh day 0 was sinilar to fresh platelets. Incorporation of (C-14)-AA on phosphatidyl inositol (FI) decayed fron 12.4+/-1.5 on day 0, to 7.9+/-0.9 on day 3 (p 0.001), While the percentage attached on phosphatidylserine (PS),increased fron 5.3+/-0.9 to 8.8+/-1.5 (p 0.001). There were not any changes fron day 3 to 5.On day 0,17.7+/-5.2X of radiactlvity was released fron phospholipids by thronbin. This anount decreased to 7.3+/-2.5X (p 0.01) on day 5. I^xaiment in breakdown of both PI and phosphatidylcholine (PC) was detected. Generation of phosphatidic acid (PA) by thronbin, decreased fron 2.6+/-0.4X of total radiactlvity on day 0 to 1.4+/-0.3X on day 3 (p 0.001) and 0.9+/-0.2X on day 5 (p 0.01). Ve did not find changes in TxB2 and HHT, but HETE decayed fron 7.2+/-2.9X on day 0, to 2.3t/-0.9% on day 5 (p 0.01).We concluded that both activities of phospholipases A-2 and C are affected by storage.
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De Chaffoy de Courcells, D., and F. De Clerck. "THE EFFECT OF A COMBINED TXA2SYNTHETASE AND TXA2/PROSTAGLANDIN ENDOPEROXIDE RECEPTOR BLOCKER(R 68 070)ON THE ACTIVATION OF EXCITATORY RECEPTOR-COUPLEDPHOSPHOLIPASE C IN HUMAN PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643758.
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Prostaglandin endoperoxides (PGEND) and thromboxane A2 (TxA2)contribute to the activation of platelets, involving inositol-containing phospholipids as a signal transducing system. A primary step in this signal transduction consists of the activation of phospholipase C, which then yields diacylglycerol and inositol phosphates;diacylglycerol is subsequently phosphorylated to phosphatidic acid (PA). In platelets prelabelled with [32P] orthophosphate,receptor activation is quantitatively reflected by an increased formation of [32P]-PA.Using this assay, the relativeimportance of endogenously generated PGEND and TxA2 for the subsequent PA-formation was analysed by means of pharmacological manipulations. R 68 070, an oxime-alkanecarboxylic acid derivative combining specific TxA2 synthetase inhibition with TxA2/PGEND receptor blockade in one molecule (1 x 10-6M) inhibited the formation of PA in collagen-stimulated platelets; by contrast, synthetase inhibitors without receptor effect (da-zoxiben, OKY-1581,1x 10-6M) increased the PA-response tocollagen.Using U 46619 as a stimulus, R 68 070 as well as BM 13177, a receptor blocker withouteffect on synthetase (1 x 10-6 M)both reduced the PA-response to the same extent while OKY-1581 (1 x 10-6 M) was ineffective. The phospholipid response induced by serotonin, vasopressin or PAF were not affected by R 68 070, demonstrating its specificity for the prostanoid system.From these data we suggest that selectiveinhibition of TxA2 synthetase does not prevent activation of excitatory platelet receptors for arachidonate metabolites. Effectiveness was only obtained by combined TxA2 synthetase/PGEND receptor blockade.
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Huzoor-Akbar, H., and Khursheed Anwer. "EVIDENCE THAT ABNORMAL PLATELET AGGREGATION IN SPONTANEOUSLY HYPERTENSIVE RATS IS LINKED WITH PHOSPHOINOSITIDES TURNOVER AND PHOSPHORYLATION OF 47,000 DALTON PROTEIN." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643810.
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We have shown earlier that abnormal platelet aggregation in spontaneously hypertensive rats (SHR) is not caused by prostaglandins (Thromb. Res. 41, 555-566, 1986). In this study platelets from SHR and normotensive (Wistar Kyoto, WKY) rats were used to examine the role of phosphoinositides (Pins) and protein phosphorylation in increased platelet activation in hypertension. Thrombin (0.05 U/ml) induced rapid hydrolysis of phosphatidylinositol-4,5-bis-phosphate (PIP2), phosphatidyl-inositol-4-phosphate (PIP), and phosphatidylinositol (PI) in (32p)-pO4 labeled platelets. However, significantly greater hydrolysis of PIP2 and PI was seen in SHR platelets than in WKY platelets (see Table). Thrombin also caused two- to three-fold increased accumulation of phosphatidic acid (PA) in SHR platelets than in WKY platelets (see Table).Thrombin caused phosphorylation of 18,000 Dalton (P18) and 47, Dalton (P47) proteins in SHR and WKY Platelets. Significantly increased phosphorylation of P47 was seen at 5, 15, 60 and 240 seconds of incubation with thrombin in SHR platelets (60%, 68%, 98% and 91%) than in WKY platelets (13%, 37%, 44% and 47%). The extent of P18 phosphorylation was same in both SHR and WKY platelets. Aspirin (500 uM) did not affect phosphorylation of P47 or P18 in SHR or WKY Platelets. These data lead us to suggest that increased turnover of Pins and increased phosphorylation of P47 are involved in abnormal platelet aggregation in SHR (Supported in part by the COHC grant #86-01-A and the Ohio University College of Osteopathic Medicine).
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Setty, B. N. Y., and M. J. Stuart. "THE MITOGENIC EFFECT OF 15-HETE ON ENDOTHELIAL CELLS IS MEDIATED VIA DIGLYCERIDE KINASE INHIBITION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643946.
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We have previously demonstrated that 15-HETE, a mitogen for fetal bovine aortic endothelial cells (FBAECs), caused an accumulation of diglyceride (DG). Stimulation of DNA synthesis by 0AG (a synthetic DG analog) suggested that this mitogenic effect was mediated via elevation of cellular DG levels. In the present study we have delineated the mechanism by which 15-HETE causes DG accumulation by evaluating the effects of 15-HETE on the phosphati-dylinositol (PI) cycle. In [3H]inositol labeled cells, 15-HETE caused a decrease in PI content under both basal conditions (27%) and following A23187 stimulation (23%). The accumulation of DG and the decrease in PI suggested activation of phosphilipase C. However, no effect of 15-HETE was found on endothelial cell phos-pholipase C. A modulatory effect of 15-HETE on PI resynthesis was next evaluated using [3H] inositol. In 5 experiments, 15-HETE (30μM) inhibited the synthesis of PI in both unstimulated (51+15%, 1SD, P<0.001) and A23187 stimulated cells (80±19%, P<0.001). DG accumulation and inhibition of PI synthesis suggested a 15-HETE effect on the conversion of DG to phosphatidic acid (PA) via DG kinase. Using endothelial cell membranes as a source of this enzyme, formation of PA was nonlinear with time, suggesting an interference by PA phosphatase on PA formation. Human red cell membranes were therefore used in lieu of FBAECs as a source of DG kinase. In this system, production of PA was inhibited by 15-HETE in a concentration-dependent manner (IC50 of 22μM). This is the first report of the presence of a DG kinase inhibitor of biological origin. Our studies also delineate the mechanism by which 15-HETE exerts its mitogenic effect on endothelial cells.
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Triplett, D. A., J. T. Brant, K. Musgrave, and C. A. Orr. "RELATIONSHIP BETWEEN LUPUS ANTICOAGULANTS AND ANTIBODIES TO PHOSPHOLIPID." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643657.
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The relationship of lupus anticoagulants (LA's) to antibodies (IgG and IgM) to cardiolipin (CL), phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidic acid (PA), detected by an enzyme linked immunoassay, was examined in a series of 100 patients with well characterized LA's. 73% of patients demonstrated antibodies to one or more phospholipids; 62% were positive for CL, 57% were positive for PS, 57% were positive for PI, and 51% were positive for PA. Of the samples with antibodies to phospholipid, 32% had IgG type antibody only, 16% had IgMonly, and 52% had both IgG and IgM antibodies. Of the 100 patients,19% had a history of thrombosis, 8% had ahistory of spontaneous abortion, and 6% had a history of seizure disorder. These complications occurred in the presence (61%) and absence (39%) of detectable phospholipid antibodies. Drug-related LA's were observed in 34 patients; of these 74% were positivefor antiphospholipid antibodies and 24% hada history of thrombosis.The distribution of antibody types with drug-related LA's was similarto the overall group, with 40% IgG only, 8%IgM only and 52% both IgG and IgM These findings indicate that IgG and IgM antibodies to phospholipid are not observed in all patients with lupus anticoagulants, that thrombosis does occur in this population in the absence of detectable antibodies to phospholipid and that drug-related LA's are associated with thrombosis. Furthermore, there appeared to be little relationship between the degree of prolongation of the aPTT and the titer of anti-phospholipid antibody.
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Koutouzov, S., A. Remmal, P. Marche, and P. Meyer. "IMPAIRMENT OF PLATELET PHOSPHOINOSITIDE METABOLISM IN PRIMARY HYPERTENSION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643812.
Full textAbstract:
Blood platelets from hypertensive patients and spontaneously hypertensive rats (SHR) display multiple abnormalities when compared with cells from normotensive controls. The major features of the modified platelet profile are an enhanced rate of adhesion/aggregation in response to many stimuli, a greater sensitivity for thrombin and adrenaline to produce increases in cytoplasmic free Ca2+, and an exaggerated release reaction. Furthermore, the resting levels of cytosolic free Ca2+ ions are specifically and constantly increased. Since phosphoinositides are involved in the stimulus-response coupling mediated by intracellular Ca2+ mobilization, the metabolism of these lipids was investigated in platelets of SHR and compared with those of normotensive Wistar-Kyoto rats (WKY). Following 32P-labelling of quiescent platelets, labeled lipids were analyzed both in platelets at rest and after thrombin stimulation. In resting platelets, the 32P associated with each of the phosphoinositides and phosphatidic acid (PA) was similar in SHR and WKY indicating that both the pool size of the various lipids and their basal turnover did not differ between the two strains. By contrast, within the first seconds after thrombin stimulation (10-60 sec), the dose-response and time-course curves of agonist-induced increase in 32P-PA were markedly shifted to the left and reached higher equilibrium levels in SHR. Since thrombin-induced 32P-PA formation is held as the most sensitive index of phospholipase C activity, our results indicate that this enzyme displays hyperreactivity in SHR (vs WKY). It is therefore likely that in SHR, the enhanced physiological responses (serotonin secretion, aggregation) that we observed under the same experimental conditions may be related to an increased formation of Phospholipase C products (inosi-toltriphosphate and diacylglycerol) which are the two second messengers responsible for internal Ca2+ mobilization and activation of protein kinase C, respectively. Therefore, these data suggest that the hypersensitivity of Phospholipase C may be involved in the overall alteration of cell calcium handling and hence in the SHR platelet responses.
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Holmsen, Holm, Ole-Bjørn Tysnes, Adrie J. M. Verhoeven, Vidar M. Steen, Lindsey J. Moore, and Sissel Rongved. "INHIBITION BY NEOMYCIN OF AGONIST-INDUCED POLYPHOSPHOINOSITIDE METABOLISM AND RESPONSES IN HUMAN PLATELETS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644521.
Full textAbstract:
Signal processing in platelets seems to involve polyphosphoinositide (PPI) metabolism, although direct coupling between PPI metabolism and responses has not been proved. Neomycin binds tightly to PPIs and has been used to probe the involvement of PPI metabolism and responses in platelets. Neomycin(SO4)3 powerfully inhibited ADP- and adrenaline-induced aggregation of platelets in PRP. This was partly due to the sulphate anion; the chloride form was therefore prepared. Platelets were prelabelled in PRP with 32P-Pi. and transferred by gel filtration to a calcium-free Tyrode’s solution (GFP). Increasing concentrations (2-5 mM) of neomycinCl6 caused progressive inhibition of thrombin-induced aggregation, dense granule secretion, acid hydrolase secretion and formation of 32P-phosphatidic acid (PA); the inhibition was immediate, not affected by aspirin and counteracted by increasing thrombin concentrations. Incubation of neomycin (up to 5 mM) with this GFP or with P-Pi. On GFP prepared from unlabelled PRP had no effect on the P content of ATP, phosphatidylinositol-4-phosphate (PIP) or phosphatidylinositol-4,5-bisphosphate (PIP ). Increasing neomycin concentrations caused progressive inhibition of the thrombin-induced init^l (10 sec) decrease, but not of the late (90 sec) incg^ase i-n P-PIP2 while they enhanced the increase in P-PIP. Similar results were obtained ^th collagen and PAF. Both the increase in cytosolic Ca and pH (measured by INDO-I and BCECF, respectively) induced by thrombin were inhibited progressively by increasing concentrations of neomycin. These results are in support for a direct involvement of PPI metabolism in the stimulus-response coupling below the receptor level. However, the failure of neomycin to affect turnover of PIP and PIP2 in nonstimulated platelets suggests that the aminoglycoside does not penetrate the membrane, and only become available to PPI during stimulation.
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Authi, K. S., B. J. Evenden, and N. Crawford. "ACTION OF GTPγS [GUANOSINE 5∲-0-(3-THIOPHOSPHATE)] ON SAPONIN-PERMEABILISED PLATELETS: INVOLVEMENT OF 'G' PROTEINS IN PLATELET ACTIVATION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644514.
Full textAbstract:
Certain ligand-receptor interactions at cell surfaces lead to the phospholipase-C (PLC) hydrolysis of phosphatidyl inositol (4.5) bisphosphate (PIP2). The products serve as intracellular second messengers, e.g. inositol (1.4.5) trisphosphate (IP3) releases Ca2+ from intracellular stores and diacylglycerol activates protein kinase-C. From studies using GTP and analogues (e.g. GTPγS) there is evidence of a key role for a guanine nucleotide binding protein(s) as a link between receptors and PIP2 hydrolysis. We report the actions of GTPγS on washed human platelets permeabilised with saponin (12-14 μg/ml) to allow penetration of low MWt polar substances. The responses to GTPγS are dose dependent (range 9-60 μM) and at 60 μM the agent induces shape change, aggregation and the secretion of 50% of previously incorporated [14C]-5HT. No effect of GTPγS is seen with intact cells. Shape change occurs 25-30 sec after GTPγS; aggregation and secretion is complete after 3 min. When GTP was used (up to 135 μM) with similarly permeabilised platelets no responses were initiated. Phosphatidylinositol turnover was monitored using 32P-labelling before permeabilisation. The addition of 90 μM GTPγS resulted in a 143 ± 23% (n=4) increase in 32P-phosphatidic acid (PA) with respect to the basal levels of “saponised control” cells. These findings suggest that GTPγS stimulates PLC activity through a ‘G’ protein interaction. The GDP analogue (GDPβS) produced no activation responses in saponised platelets but inhibited responses induced by GTPγS in a dose dependent manner (0-480 μM, max inhibition 480 μM). At 960 μM, GDPβS totally inhibited aggregation and secretion initiated by low doses of thrombin (0.1 U/ml) and collagen (1 μg/ml). Identical inhibition by GDPβS of thrombin and collagen-induced activation of intact platelets was observed indicating membrane penetration of this analogue. Shape change effects were not inhibited by GDPSS. The inhibitory effects of GDPSS towards thrombin and collagen induced secretion could be progressively overcome at higher doses of thrombin (0.2 U/ml - 2 U/ml) and collagen (5 μg/ml - 60 μg/ml) suggesting that at higher concentrations these agonists may exert effects through 'G' protein-independent mechanisms.
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de Chaffov de Courcelles, D., F. De Clerck, and P. Roevens. "EVALUATION OF THE PROPOSED FUNCTIONS OF PROTEIN KINASE C IN PLATELET SIGNAL TRANSDUCTION BY THE USE OF A DIACYLGLYCEROL KINASE INHIBITOR." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644632.
Full textAbstract:
Protein kinase C is suggested to play a major role in propagation as well as in termination of excitatory signal transduction in the platelet. Most of its properties were discovered by the use of synthetic diacylglycerol analogs or phorbol esters that directly stimulate protein kinase C. It is, however, unknown to what extent activation of the protein kinase C by these exogenously added compounds can be compared to that after receptor activation. To evaluate the role of protein kinase C in excitatory signal transduction, we transiently elevated the endogenous diacylglycerol level after receptor activation by the use of a diacylglycerol kinase inhibitor (R 59 949). On addition of the agonist vasopressin to platelets prelabeled with [32P] orthophosphate, 32P-phosphatidic acid (PA) formation was inhibited by R 59 949 in a dose-dependent manner (IC50 α 10−6 M). Vasopressin induced formation of 32P-phosphatidylinositol-4’-phosphate (PIP) and the phosphorylation of the 40 k Da protein (major substrate of the protein kinase C) were increased in the presence of the compound. In platelets prelabeled with [3H]-inositol, the agonist-induced formation of all the water-soluble inositol phosphates was inhibited in the presence of the diacylglycerol kinase inhibitor and Li+. Vasopressin induced increase in intracellular Ca2+ was lower in the presence of R 59 949. The platelet shape change induced by a threshold concentration of vasopressin was reduced by the compound. By contrast, the rate and the maximum of the first-wave aggregation was enhanced in the presence of R 59 949.These data evidence that protein kinase C, stimulated by endogenously generated diacylglycerol after receptor activation, plays a major inhibitory role on the primary steps of signal transduction since its activation reduces i) phospholipase C activity and ii) the increase in intracellular Ca2+ and the concomitant shape change reaction. The inhibitory role of protein kinase C on signal transduction is largely independent of its stimulatory role on platelet aggregation. Our data further confirm that stimulation of protein kinase C induces the formation of PIP but questions the role of the kinase in the breakdown process of inositoltrisphosphate.