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At least 631 records · Page 35Linked to original sources
PubMed1987

Arginine-vasopressin stimulates the formation of phosphatidic acid in rat Leydig cells.

Arginine-vasopressin (AVP) stimulated the formation of labelled phosphatidic acid (PA) in [14C]arachidonic acid-prelabelled rat Leydig cells. After addition of 10(-6)M AVP [14C]arachidonoylphosphatidic acid reached a maximum within 2 min. The increase was dose-dependent (10(-11)-10(-6)M). No change in labelling of other phospholipids and diacylglycerol could be detected. The V1 antagonist dPTyr(Me)AVP inhibited in a dose-dependent manner the AVP-stimulated accumulation of PA. The V2 agonist dPVDAVP was without effect. The present results suggest that AVP binds to V1 receptors in rat Leydig cells resulting in stimulation of PA turnover. We suggest that the AVP-stimulated PA formation is an indication of phosphoinositide turnover.

Animals↗
PubMed1993

Induction of phosphatidic acid by fibroblast growth factor in cultured baby hamster kidney fibroblasts.

Basic fibroblast growth factor (bFGF/FGF-2) is a strong mitogenic inducer of cultured baby hamster kidney (BHK) cells. When cultured BHK cells were stimulated with FGF-2, phosphatidic acid (PA) was induced within 2 min, peaked at 5 min and gradually decreased. Phospholipase D (PLD) was also mitogenic for cultured BHK cells and this effect was mediated via PA. The possibility that PA induction by FGF-2 is an essential signaling step for BHK cell proliferation is discussed.

Animals↗
PubMed1993

Phosphatidic acid induces the respiratory burst of electropermeabilized human neutrophils by acting on a downstream step of protein kinase C.

Phosphatidic acid (PA) dose-dependently induced superoxide (O2-) production of electropermeabilized human neutrophils but not of intact neutrophils, indicating that PA induces the activation of NADPH oxidase by acting on an intracellular target. The O2- production by PA was not inhibited by protein kinase C (PKC) inhibitors, such as staurosporine and calphostin C, and an inhibitor of PA phosphohydrolase, propranolol. These observations suggest that the activation of the oxidase by PA is independent of the activity of PKC and may dominate the activation by diacylglycerol which is formed from PA via the action of PA phosphohydrolase. Furthermore, the production by PA, as well as that by phorbol myristate acetate, was inhibited by cyclic AMP and GDP beta S. Therefore, PA seems to act at a site downstream of PKC.

Cell Membrane Permeability↗
PubMed1993

Enhancement of phospholipase A2 activation by phosphatidic acid endogenously formed through phospholipase D action in rat peritoneal mast cell.

Contribution of phosphatidic acid (PA) generated by activated phospholipase (PL) D to PLA2 activation was studied in rat peritoneal mast cells. Exogenous didecanoyl PA induced arachidonate liberation in the permeabilized cells which was inhibited by p-bromophenacyl bromide. Upon exposure of the cells to ethanol in a high enough concentration to prevent PA formation, A23187-induced arachidonate liberation was suppressed by 50% and the rest was completely inhibited by p-bromophenacyl bromide. In contrast, propranolol, which enhanced PA accumulation, significantly increased the arachidonate liberation. These results suggest that A23187-induced PLA2 activation may be potentiated, at least in part, by PA generated through PLD action.

Animals↗
PubMed1996

Identification of phosphatidate phosphohydrolase purified from rat liver membranes on SDS-polyacrylamide gel electrophoresis.

Phosphatidate phosphohydrolase (PAP; EC 3.1.3.4) insensitive to N-ethylmaleimide was partially purified from rat liver membranes by a combination of chromatographic methods, immunoabsorption and glycerol gradient centrifugation. The specific activity was increased more than 600-fold over that of the membrane extract. Enzyme antibodies precipitating more than 80% of PAP were obtained and used for the identification of PAP protein on SDS-polyacrylamide gels employing the immunodetection method of Muilerman et al. [(1982) Anal. Biochem. 120, 46-51]. By this approach PAP was localized as a 31 kDa polypeptide.

Animals↗
PubMed1991

Stimulation of human platelets with low concentrations of thrombin: evidence for equimolar accumulation of inositol trisphosphates and phosphatidic acid.

1. Gel-filtered human platelets prelabeled with [32P]Pi or [3H]glycerol were exposed to 0-0.3 U/ml of thrombin and analyzed for radioactivities and masses in the phosphoinositides, inositol trisphosphates (IP3), phosphatidic acid (PA) and diacylglycerol (DAG) at 15 and 180 sec of stimulation. 2. At thrombin concentrations below 0.1 U/ml, PA and IP3 accumulated in equimolar amounts. 3. The production and disappearance of the metabolites of the polyphosphoinositide cycle was balanced during 180 sec of stimulation with 0.03-0.1 U/ml of thrombin. 4. Under these conditions no increase in [3H]DAG or [3H]monoacylglycerol could be detected. 5. The data indicate that all DAG is converted to PA and support our conclusion that phosphatidylinositol 4,5-bisphosphate represents the major source for production of DAG upon stimulation of human platelets with low concentrations of thrombin.

Blood Platelets↗
PubMed1986

Effect of ethanol on receptor-stimulated phosphatidic acid and polyphosphoinositide metabolism in mouse brain.

The effects of chronic ethanol consumption as well as the effects of ethanol added in vitro on phosphoinositide metabolism were determined in mouse forebrain. [32P] incorporation into synaptosomal phosphatidic acid (PhA) was stimulated through both M1 muscarinic cholinergic and alpha 1 adrenergic receptor activation. Similarly, [3H]inositol 1-PO4 accumulation in brain slices was stimulated through these same receptors, but could also be stimulated by histamine1 receptor activation. In mice made physically dependent to ethanol, the magnitude of receptor-mediated [32P] incorporation in PhA did not differ from that of control animals. However, ethanol (100mM) added in vitro to synaptosomes from control mice significantly inhibited the carbamylcholine stimulated PhA response, but had no effect on the response to norepinephrine. Carbamylcholine stimulated [32P] incorporation into PhA, however, was no longer significantly inhibited by the addition of 100mM ethanol to synaptosomes from physically dependent-tolerant animals indicating that a cellular tolerance had developed. In contrast, receptor mediated [3H]inositol 1-PO4 accumulation in brain slices was not significantly affected by either chronic ethanol treatment or the in vitro addition of ethanol as high as 200mM. It is concluded that the muscarinic cholinergic stimulation of [32P] incorporation into PhA, but not [3H]inositol 1-PO4 accumulation is relatively more sensitive to the direct effects of ethanol than are the other receptor mediated phospholipid responses examined in the present investigation and that this sensitivity is lost in animals made behaviorally tolerant and physically dependent to ethanol.

Animals↗
PubMed1988

Inhibition of apolipoprotein secretion and phosphatidate phosphohydrolase activity by eicosapentaenoic and docosahexaenoic acids in the perfused rat liver.

Infusion of albumin-bound eicosapentaenoic acid (EPA) docosahexaenoic acid (DHA), or oleic acid (OA) in perfused rat livers was carried out for two hours at a rate that maintained the perfusate concentration at 1 mmol/L. When compared with fatty acid-poor albumin alone, triacylglycerol (TAG) output was not significantly increased with DHA or EPA, whereas OA infusion resulted in a twofold increase. Incorporation of labeled leucine into VLDL apo B-100, apo B-48, apo E, and apo Cs was decreased by 50% by DHA or EPA compared with OA. The total phosphatidate phosphohydrolase activity was decreased by 35% with DHA or EPA compared to oleic acid or albumin alone. In no case was there a significant change in the distribution of activity between the microsomal and cytosolic factions. Fatty acid infusion did not significantly change the liver TAG content. Total liver lipids, microsomal lipids, and lipids of secreted VLDL were enriched with the infused fatty acids. The degree of enrichment for secreted TAG averaged 24% for OA and 36% for DHA or EPA. The effects of DHA and EPA on PPH activity and on apo B secretion in feeding experiments with marine oils rich in these acids may relate to changes in the fatty acid composition of liver membranes.

Animals↗
PubMed1987

Effect of BN 52021, a specific antagonist of platelet activating factor (PAF-acether), on calcium movements and phosphatidic acid production induced by PAF-acether in human platelets.

32P-labelled human platelets loaded with quin 2 and pretreated with aspirin were stimulated with 1-100 nM platelet activating factor (PAF-acether or 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) in a medium containing the ADP-scavenging system creatine phosphate/creatine phosphokinase. Under these conditions, PAF-acether evoked a characteristic fluorescence change allowing to quantify elevations in cytoplasmic free Ca2+ from internal stores (Ca2+ mobilization) or from external medium (Ca2+ influx), as well as an increased production of phosphatidic acid, reflecting phospholipase C activation. These effects, which can be attributed to PAF-acether only and not to released products such as ADP or thromboxane A2, were strongly inhibited in a dose-dependent manner by BN 52021, a specific antagonist of PAF-acether isolated from Ginkgo biloba. As the drug remained inactive against the same effects elicited by thrombin, it is concluded that BN 52021 does not interfere directly with the mechanism of transmembrane signalling involving inositol-phospholipids or (and) some putative receptor-operated channels, but rather acts on the binding of PAF-acether to its presumed membrane receptor.

Aminoquinolines↗
PubMed1984

Platelet-activating factor phosphatidate, but not platelet-activating factor, is a powerful calcium ionophore in the human red cell.

Platelet-activating factor (1-0-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, PAF) is a potent inducer of shape-change, aggregation and secretion in platelets. PAF causes a rapid increase in intracellular calcium, but has no calcium gating effect in intact lipid bilayers. Human red cells (RBC) did not metabolize either PAF or PAF-phosphatidate (PAF-PA). While PAF (10 microM) was devoid of calcium ionophoretic activity, PAF-PA (1-5 microM) stimulated calcium influx into intact human RBC. In addition, PAF-PA (1-10 microM), but not PAF (10 microM), elicited a series of satellite effects related to the rise of intracellular calcium: 1) increased efflux of intracellular potassium (Gàrdos effect); 2) alkalinization of unbuffered RBC suspensions; 3) stimulation of ATP consumption and production, and enhancement of glycolytic flux with crossover at the glyceraldehyde 3-phosphate dehydrogenase step. These effects exactly duplicate those brought about by the calcium ionophore A23187. The ionophoretic potency of PAF-PA was about half that of A23187. Approximately the same concentrations of PAF-PA as those that stimulate calcium influx into RBC elicit full aggregatory response in human platelets. It is possible that transformation of PAF into PAF-PA by the combined action of phospholipase C and diacylglycerol kinase contributes to the increase of calcium influx in platelets.

Calcium↗
PubMed1991

Molecular species analysis of 1,2-diacylglycerols and phosphatidic acid formed during bombesin stimulation of Swiss 3T3 cells.

Swiss 3T3 cells were labelled with [3H]glycerol and stimulated with bombesin over a time course of 20 min. The individual 1,2-diacylglycerols produced were quantified by acetylation followed by analysis by HPLC and argentation chromatography. The major phospholipids and phosphatidic acid were acetolysed and then analysed in the same manner. The data show that even at an early time of stimulation (30 s), stimulated diacylglycerol formation comes from at least two sources--phosphoinositides and phosphatidylcholine.

Animals↗
PubMed1992

Insulin effect on isolated rat hepatocytes: diacylglycerol-phosphatidic acid interrelationship.

It is widely accepted that insulin action does not involve inositol phospholipid hydrolysis through the stimulation of a phosphatidylinositol-specific phospholipase C (PI-PLC). This consideration prompted us to investigate the insulin effect on the mechanism leading to the accumulation of diacylglycerol (DAG) and phosphatidic acid (PA) in rat hepatocytes. Basically, insulin induces: (i) a significant increase of both [3H]glycerol and fatty acid labelling of DAG; (ii) a significant increase of PA labelling preceding DAG labelling and paralleled by a decrease of phosphatidylcholine (PC) labelling. These observations, which suggest an insulin-dependent involvement of a phospholipase D, are strengthened by the increase of PC-derived phosphatidylethanol in presence of ethanol. Finally, the observation that the PA levels do not return to basal suggests that other mechanisms different from PC hydrolysis, such as the stimulation of direct synthesis of PA, may be activated.

Animals↗
PubMed1993

Characterization of phosphatidic acid phosphohydrolase in neutrophil subcellular fractions.

This investigation was designed to confirm the presence of PA phosphohydrolase in human neutrophils and to determine the distribution and characteristics of the enzyme in soluble and particulate subcellular fractions of disrupted neutrophils. Enzyme activity was detected in unseparated extracts of sonicated neutrophils. The majority of the recovered activity was recovered in a particulate fraction rich in neutrophil plasma-membrane markers; moderate levels (20%) of the total activity were recovered in the cytosol. While Mg2+ markedly potentiated the cytosolic but not the particulate activity, Ca2+ moderately inhibited both the cytosolic and particulate enzymes. The plasma-membrane-associated activity was absolutely dependent on detergent (0.5% Triton X-100) and displayed an apparent Km of 62 microM for phosphatidic acid. Enzyme activity was markedly inhibited by NaF, not influenced by excess glycerophosphate and slightly attenuated by propranolol, an inhibitor of PA phosphohydrolase in other systems. Preincubation of plasma membranes with N-ethylmaleimide at concentrations up to 25 mM had little effect on enzyme activity. However, activity in cytosolic and microsomal fractions of neutrophils were completely abolished by preincubation with N-ethylmaleimide at concentrations of less than 5 mM. We conclude that neutrophils possess a potent PA phosphohydrolase localized in their plasma membranes. Metabolism of cellular second-messengers by this enzyme may exert a profound effect on the functions of stimulated neutrophils.

Calcium↗
PubMed1990

Initial responses of a clonal osteoblast-like cell line, MOB 3-4, to phosphatidic acid in vitro.

A number of studies have shown membrane phospholipid metabolism to have an important role in biological mineralization. We considered the effects of exogenously applied phosphatidic acid (PA), a minor component of membrane phospholipids, on an osteoblast-like cell line, MOB 3-4. Exogenous PA (10-40 micrograms/ml) raised the level of cytoplasmic free Ca2+ [( Ca2+]i), independent of the level of extracellular Ca2+, in a dose-dependent fashion, and this Ca2+ response to PA gradually fell on serial application of PA. In a dose-dependent manner, exogenous PA also increased inositol 1,4,5-trisphosphate (IP3) accumulation and cytoplasmic pH, but decreased basal cAMP level. This cytoplasmic alkalinization was inhibited by pretreatment with nonspecific protein kinase C (PKC) inhibitors, such as sphingosine or H-7. A long-term incubation with PA increased alkaline phosphatase (ALP) activity and cell proliferation. Exogenous PA thus appeared to increase IP3 accumulation by activating phospholipase C, raise [Ca2+] by releasing Ca2+ from intracellular stores, induce cytoplasmic alkalinization via a PKC-dependent mechanism, and simultaneously decrease basal cAMP level. We suggest that these initial responses may be responsible for the increase in ALP activity and the proliferation of PA-treated MOB 3-4 cells.

Alkaline Phosphatase↗
PubMed1992

Brain phosphatidic acid and polyphosphoinositide formation in a broken cell preparation: regional distribution and the effect of age.

The effect of age on phosphate incorporation into phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid (PA) was studied. Lysed crude synaptosomal fractions of different brain regions of 3-month-old and 32-month-old Brown Norway rats were used. The brain regions tested were the hippocampus, frontal cortex, occipital/parietal cortex, entorhinal/pyriformal cortex, striatum/septum, thalamus and hypothalamus. The individual specific phosphorylating activities were unevenly distributed within the brain of Brown Norway rats. Strikingly, the distribution of phosphate incorporation into PIP2 was opposite from that of phosphate incorporation into PA. Phosphate incorporation into PA decreased (-15%) with age in almost all brain regions tested, whereas phosphate incorporation into PIP2 decreased with age only in the frontal cortex (-20%) and in the hypothalamus (-8%). The effects of age may reflect a deterioration of phosphoinositide metabolism, with its function in signal transduction coupled to receptors via G-proteins, in the brain regions involved. In addition, there was an age related decrease in protein content and total phospholipid phosphorus content of lysed crude synaptosomal preparations of all brain regions. The high correlation between the changes in these parameters may be indicative of a decrease in the number or size of synaptosomes with age in the brain regions involved.

Adenosine Triphosphate↗
PubMed1994

Phosphatidic acid promotes phosphoinositide metabolism and DNA synthesis in cultured cortical astrocytes.

The addition of exogenous phosphatidic acid (PA) to cultured cortical astrocytes prelabelled with [3H]inositol resulted in the accumulation of intracellular [3H]inositol phosphates (IP) in a concentration-dependent (EC50 = 20 microM) manner. Analysis of the individual IPs formed following a PA challenge revealed a rapid but transient generation of [3H]inositol trisphosphate (IP3) indicating the involvement of phosphatidylinositol 4,5-bisphosphate (PIP2) breakdown in this response a fact which was confirmed when the recovery of radiolabel in membrane phosphoinositides was assessed. PA's ability to stimulate IP3 accumulation was found to be dependent upon its acyl-chain length. Dioleoyl-PA (C18:1) was equally as effective as PA from egg yolk lecithin in this respect whilst dipalmitoyl-PA (C16:0) was less so and dimyristoyl-PA (C14:0) and dilauroyl-PA (C12:0) were without effect. In subconfluent, serum-deprived cultures, PA was found to increase DNA synthesis following a 48 h exposure period. This effect was observed over the same concentration range used to measure phosphoinositide breakdown and was found to be mediated by the activation of protein kinase C. As with its effect on phosphoinositide metabolism, PA's ability to promote DNA synthesis was correlated with its acyl-chain length. These data show that PA is capable of stimulating both phosphoinositide metabolism and DNA synthesis in cultured astrocytes possibly via the activation of specific membrane receptors. However, the precise relationship between these events remains to be elucidated.

Animals↗
PubMed1994

Agents that increase phosphatidic acid inhibit the LH-induced testosterone production.

The results of the present study point to phosphatidic acid (PtdOH) as a possible intracellular messenger, which might be involved in local modulation of testicular testosterone production in vivo. Propranolol (27-266 microM) induced an increased level of [3H]PtdOH in isolated rat Leydig cells, prelabeled with [3H]myristate, and at the same time a strong dose-dependent inhibition of the acute testosterone production stimulated by luteinizing hormone (LH). The inhibition was not bypassed by the addition of dibutyryl-cAMP but was overcome, when 22(R)-hydroxycholesterol was added as a direct substrate for cytochrome P-450 side chain cleavage enzyme. Thus, the inhibition appears to be exerted at a point distal to cAMP-generation but before the first enzyme in the testosterone synthetic pathway. Treatment with other agents (4 beta-phorbol 12-myristate 13-acetate (PMA), A23187, and sphingosine) giving rise to increases in the PtdOH-level resulted in the inhibition of the LH-induced testosterone formation as well, thus indicating a connection between the two effects. Furthermore, we were able to demonstrate a highly significant correlation between the PtdOH-increase and the inhibition of the LH-stimulated testosterone production. This may suggest a causal relationship between these two parameters.

Animals↗
PubMed1995

Phosphatidic acid activation of protein kinase C in LA-N-1 neuroblastoma cells.

Phosphatidic acid (PA), a hydrolytic product of phospholipase D activity, stimulated cytosolic protein kinase C (PKC) activity when LA-N-1 neuroblastoma cells in culture were treated with PA, without translocating the enzyme to the membrane. Treatment of cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) translocated and activated PKC in a dogmatic manner. Partially purified PKC activity derived from LA-N-1 neuroblastoma cells was stimulated by PA alone or in the presence of phosphatidylserine or TPA, without affecting [3H]phorbol dibutyrate binding, indicating that the site of action of PA was different from the phorbol ester or diacylglycerol binding site. These results suggest an unorthodox pattern of PKC stimulation mediated by PA which appears to be yet another mode of PA signal transduction.

Binding, Competitive↗