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PubMed1988

Interaction of polymyxin B1 and polymyxin B1 nonapeptide with phosphatidic acid monolayer and bilayer membranes.

The interactions of the antibiotic polymyxin B1 and its enzymatic cleavage product polymyxin B1 nonapeptide with phosphatidic acid monolayers and with bilayer membranes were investigated. Temperature-dependent pressure-area analysis of the monolayer reveals a linear increase of the lipid mean molecular area in the liquid condensed state for polymyxin concentrations between 10(-8) and 4 x 10(-7) M. Depending on the surface pressure, the area increase amounts to 30-70 A2. A linear dependence was also observed in the liquid expanded state but saturation is reached already at 10(-7) M polymyxin. The adsorption of polymyxin to phosphatidic acid bilayers is also linear and of a Langmuir type. Saturation is reached at a 1:4 polymyxin/lipid molar ratio. Polymyxin induces a phase separation in phosphatidic acid monolayers which was concluded from the thermotropic phase transition curves. In agreement with earlier bilayer experiments a second lowered phase transition appears in the presence of polymyxin. These fluidized domains again exhibit a linear polymyxin uptake comparable to the one of the liquid expanded monolayer at a temperature, where the undisturbed lipid is still in the condensed state. Polymyxin nonapeptide also causes an expansion of phosphatidic acid monolayers but only by maximally 10 A2. The thermotropic phase transition of the monolayer is reduced and considerably broadened by the nonapeptide. In phosphatidic acid bilayers we observed a decrease of the lipid phase transition temperature by 24 degrees C. The lateral chain packing is considerably disturbed by the peptide part of polymyxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1996

Phosphatidic acid: a lipid messenger involved in intracellular and extracellular signalling.

Generated during the initial phases of cell signalling, phosphatidic acid has been implicated as a messenger involved in the activation of cellular kinases and phospholipases as well as certain proto-oncogene products and low-molecular-weight G-proteins. Although many of the reported effects of phosphatidic acid can be attributed to metabolites generated by cellular hydrolases, the parent compound clearly possesses important biological activities. However, instead of acting as a ubiquitous second messenger mediating signalling events shared by a wide variety of cells, in many systems the phospholipid seems to function specifically, regulating unique functions confined to specialized groupings of cells. One such function is neutrophil superoxide generation, which is induced when phosphatidic acid, generated by activated phospholipase D (PLD), facilitates the interaction of a cytoplasmic low-molecular-weight G-protein with dormant, membrane-bound reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Positioned on the outer surface of the plasma membrane of triggering cells, phosphatidic acid potentially mediates the "juxtacrine" stimulation of cells in direct contact. This review critically evaluates the known biological effects of phosphatidic acid as opposed to functions induced by its metabolites and addresses the mechanisms by which these effects are specifically induced by this phospholipid.

Calcium↗
PubMed1998

Differential influence of rat liver fatty acid binding protein isoforms on phospholipid fatty acid composition: phosphatidic acid biosynthesis and phospholipid fatty acid remodeling.

The ability of two rat liver fatty acid binding protein (L-FABP) isoforms to influence microsomal phosphatidic acid biosynthesis, a key intermediate in glycerolipid formation, and phospholipid fatty acid remodeling was examined in vitro. Isoform I enhanced microsomal incorporation of [1-14C]-oleoyl-CoA into phosphatidic acid 7-fold while isoform II had no effect relative to basal. In contrast, isoform II enhanced microsomal incorporation of [1-14C]-palmitoyl-CoA into phosphatidic acid 4-fold while isoform I had no effect. These results suggest that each L-FABP isoform selectively utilized different acyl-CoAs for glycerol-3-phosphate esterification. Both isoforms stimulated phosphatidic acid formation by increasing glycerol-3-phosphate acyltransferase activity, not by increasing lysophosphatidic acid acyltransferase activity. Furthermore, the effects of L-FABP on phosphatidic acid biosynthesis could not be correlated with protection from acyl-CoA hydrolysis. L-FABP isoforms also influenced phospholipid fatty acid remodeling in a phospholipid-dependent manner. Isoform I preferentially enhanced oleate and palmitate esterification into phosphatidylethanol-amine, while isoform II stimulated esterification into phosphatidylcholine, phosphatidylserine and sphingomyelin. Taken together, these data demonstrated a unique role of each L-FABP isoform in modulating microsomally derived phospholipid fatty acid composition. (c) 1998 Elsevier Science B.V.

Acyl Coenzyme A↗
PubMed1993

Correlation of phospholipid structure with functional effects on the nicotinic acetylcholine receptor. A modulatory role for phosphatidic acid.

Fourier transform infrared spectroscopy is used to characterize specific interactions between negatively charged lipids, such as phosphatidic acid, and the purified nicotinic acetylcholine receptor from Torpedo californica. The specific interaction of phosphatidic acid with acetylcholine receptor is demonstrated by the receptor-induced perturbation of the lipid ionization state, which is monitored using Fourier transform infrared bands arising from the phosphate head group. The acetylcholine receptor shifts the pKa of phosphatidic acid molecules adjacent to the receptor to a lower value by almost 2 pH units from 8.5 to 6.6. Decreased pH also leads to changes in ion channel function and to changes in the secondary structure of the acetylcholine receptor in membranes containing ionizable phospholipids. Phospholipase D restores functional activity of acetylcholine receptor reconstituted in an unfavorable environment containing phosphatidylcholine by generating phosphatidic acid. Lipids such as phosphatidic acid may serve as allosteric effectors for membrane protein function and the lipid-protein interface could be a site for activity-dependent changes that lead to modulation of synaptic efficacy.

Animals↗
PubMedDate not supplied

Phosphatidic acid-mediated regulation of neutrophil plasma membrane CD45-phosphotyrosine phosphatase.

CD45-phosphotyrosine phosphatase (PTPase) constitutes the major portion of thr PTPase activity within plasma membranes of neutrophilic leukocytes, where it regulates signals leading to functional activation. We have previously demonstrated that the catalytic component of neutrophil plasma membrane CD45-PTPASE is regulated by a cytosolic inactivator which itself is attenuated upon cellular stimulation, allowing enzyme translocated from granule stores to express full activity. The present study investigated mechanisms of cytosolic inactivator attenuation. Preincubation of plasma membranes of stimulated neutrophils with cytosol from resting cells resulted in a rapid loss of membrane-associated PTPase activity. Phosphatidic acid had no direct effect on plasma membrane PTPase activity but blunted in a dose dependent manner the effects of the PTPase inactivator. Inactivator attenuation was not observed with equivalent concentrations of either diacylglycerol or lysophosphatidic acid. Optimal attenuation of inactivator activity was obtained with long chain, soluble ligands, such as dicapryl phosphatidic acid. Inhibitors of neutrophil plasma membrane ecto-phosphatidic acid phosphohydrolase did not block inactivator attenuation, suggesting that phosphatidic acid and not one of its metabolites was the entity responsible. In conclusion, neutrophil plasma membrane PTPase is dynamically regulated by a cytosolic inactivator, the inhibition of which may potentiate the effects of PTPase translocated during cellular stimulation. Phosphatidic acid generated as a consequence of cellular stimulation may mediate this inhibition and thereby regulate the effects of tyrosine kinases activated during the initial phases of cell stimulation.

Cell Membrane↗
PubMed1998

Diacylglycerols and phosphatidates: which molecular species are intracellular messengers?

In eukaryotes, many receptor agonists use phospholipase-generated lipids as intracellular messengers. Receptor occupation stimulates the production of polyunsaturated 1,2-diacylglycerols by phosphatidylinositol-4,5-bisphosphate specific phospholipases C and/or of mono-unsaturated and saturated phosphatidates by phospholipase-D-catalysed phosphatidylcholine breakdown. The primary phospholipase products are rapidly metabolized: polyunsaturated 1,2-diacylglycerols are converted to polyunsaturated phosphatidates by diacylglycerol kinase; mono-unsaturated and saturated phosphatidates are dephosphorylated to give mono-unsaturated and saturated 1,2-diacylglycerols by phosphatidate phosphohydrolase. The phospholipase-generated polyunsaturated 1,2-diacylglycerols and mono-unsaturated and saturated phosphatidates appear to be intracellular messengers, whereas their immediate metabolites probably do not have signalling functions.

Animals↗
PubMed2000

Membrane lipids have multiple effects on interfacial catalysis by a phosphatidic acid-preferring phospholipase A1 from bovine testis.

We previously purified a cytosolic phospholipase A1 that could catalyze the preferential hydrolysis of phosphatidic acid in mixed-micelle assays. Here we studied the enzyme's interactions with unilamellar lipid membranes and examined effects of the lipids on enzyme binding, stability, and catalysis. A major finding was that membrane lipids could influence the stability, activity, and specificity of the enzyme under conditions where enzyme binding to the membranes was likely to be saturated. Thus, the enzyme was unstable at 37 degrees C in the absence of membranes but bound to membranes that contained anionic phosphoglycerides and could be stabilized by these membranes in the presence of albumin. The overall activity of the bound enzyme toward membrane phosphoglycerides, assayed in the presence of albumin, increased when phosphatidylethanolamine was substituted for phosphatidylcholine. Furthermore, the enzyme's catalytic preference for phosphatidic acid increased when cholesterol and diacylglycerol were included in the membranes, sn-1-stearoyl-2-arachidonoylphosphatidylethanolamine was substituted for sn-1-palmitoyl-2-oleoylphosphatidylethanolamine, and the concentration of phosphatidic acid was increased from 0 to 10 mol % of the total membrane phosphoglycerides. Finally, changes in the relative contents of phosphatidylcholine and phosphatidylserine in the membranes influenced the enzyme's catalytic preference for different molecular species of phosphatidic acid. These results provide the first available information about the enzyme's ability to interact with membranes and identify conditions that yield high enzyme activity toward membrane-associated phosphatidic acid.

Amino Acid Sequence↗
PubMed1984

Can phosphorylation of phosphatidate phosphohydrolase by a cyclic AMP-dependent mechanism regulate its activity and subcellular distribution and control hepatic glycerolipid synthesis?

Incubating the particle-free supernatant of rat liver with alkaline phosphatase decreased the activity of phosphatidate phosphohydrolase by 21-29%. When the particle-free supernatant was incubated with various combinations of Mg2+, ATP, cyclic AMP and cyclic AMP-dependent protein kinase this failed to alter significantly phosphatidate phosphohydrolase activity under the conditions employed. The incubation of hepatocytes in monolayer culture with 0.5 mM-8-(4-chlorophenylthio)adenosine 3',5'-monophosphate increased the total activity of phosphatidate phosphohydrolase as measured in vitro. This also decreased the proportion of the phosphohydrolase that was associated with the membrane fraction of the cells and increased that in the cytosolic fraction. Adding 1 mM-oleate to the hepatocytes promoted the translocation of phosphatidate phosphohydrolase from the cytosol to the membrane-associated compartment. Oleate overcame the effect of the cyclic AMP analogue in favouring the cytosolic distribution of the phosphohydrolase. These results are discussed in relation to the interaction of hormonal balance and substrate supply in controlling the synthesis of phosphatidylcholine and triacylglycerol in the liver in stress and in diabetes. It is proposed that the cytosolic phosphatidate phosphohydrolase activity represents a reservoir of potential activity that becomes expressed when the enzyme translocates to the membranes on which the synthesis of glycerolipids occurs.

Adenosine Triphosphate↗
PubMed1985

Interactions of insulin, glucagon and dexamethasone in controlling the activity of glycerol phosphate acyltransferase and the activity and subcellular distribution of phosphatidate phosphohydrolase in cultured rat hepatocytes.

Rat hepatocytes were incubated in monolayer culture for 8 h. Glucagon (10nM) increased the total phosphatidate phosphohydrolase activity by 1.7-fold. This effect was abolished by adding cycloheximide, actinomycin D or 500 pM-insulin to the incubations. The glucagon-induced increase was synergistic with that produced by an optimum concentration of 100 nM-dexamethasone. Theophylline (1mM) potentiated the effect of glucagon, but it did not affect the dexamethasone-induced increase in the phosphohydrolase activity. The relative proportion of the phosphohydrolase activity associated with membranes was decreased by glucagon when 0.15 mM-oleate was added 15 min before the end of the incubations to translocate the phosphohydrolase from the cytosol. This glucagon effect was not seen at 0.5 mM-oleate. Since glucagon also increased the total phosphohydrolase activity, the membrane-associated activity was maintained at 0.15 mM-oleate and was increased at 0.5 mM-oleate. This activity at both oleate concentrations was also increased in incubations that contained dexamethasone, particularly in the presence of glucagon. Insulin increased the relative proportion of phosphatidate phosphohydrolase that was associated with membranes at 0.15 mM-oleate, but not at 0.5 mM-oleate. It also decreased the absolute phosphohydrolase activity on the membranes at both oleate concentrations in incubations that also contained glucagon and dexamethasone. None of the hormonal combinations significantly altered the total glycerol phosphate acyltransferase activity. However, glucagon significantly increased the microsomal activities, and insulin had the opposite effect. Glucagon also decreased the mitochondrial acyltransferase activity. There was a highly significant correlation between the total phosphatidate phosphohydrolase activity and the synthesis of neutral lipids from glycerol phosphate and 0.5 mM-oleate in homogenates of cells from all of the hormonal combinations. Phosphatidate phosphohydrolase activity is increased in the long term by glucocorticoids and also by glucagon through cyclic AMP. In the short term, glucagon increases the concentration of fatty acid required to translocate the cytosolic reservoir of activity to the membranes on which phosphatidate is synthesized. Insulin opposes the combined actions of glucagon and glucocorticoids. The long-term events explain the large increases in the phosphohydrolase activity that occur in vivo in a variety of stress conditions. The expression of this activity depends on increases in the net availability of fatty acids and their CoA esters in the liver.

Acyltransferases↗
PubMed1991

Phosphatidate-dependent protein phosphorylation.

Phosphatidate-dependent protein phosphorylation was observed in soluble extracts from rat liver, brain, lung, and testis. The phosphorylation was stimulated by free Ca2+ in the range of 360-800 nM. Incubation mixtures containing phosphatidate provided markedly different profiles of protein phosphorylation from those with phosphatidylserine plus 1,2-diolein. Phosphatidate-dependent phosphorylation of a 30-kDa protein in the soluble fraction from heart was also observed. This phosphorylation did not require Ca2+. Soluble fractions from liver, testis, brain, and lung phosphorylated the 30-kDa heart protein in a phosphatidate-dependent Ca(2+)-independent manner. We propose that part of the action of phosphatidate in cells may be mediated by a protein kinase(s).

Adenosine Triphosphate↗
PubMed1996

Phosphatidic acid generation through interleukin 2 (IL-2)-induced alpha-diacylglycerol kinase activation is an essential step in IL-2-mediated lymphocyte proliferation.

Proliferation of T lymphocytes is triggered by the interaction of interleukin 2 (IL-2) with its high affinity specific receptor that is expressed on the cell surface following T lymphocyte activation. Significant advances have recently been made in identifying the multiple signals that follow IL-2 receptor occupancy, although the exact mechanism responsible for IL-2-induced proliferation remains an enigma. It has been shown previously that unique species of phosphatidic acid are rapidly produced in vivo following IL-2 binding. It was then suggested that, in contrast to other eukaryotic growth factor systems, phosphatidic acid was at least in part generated through IL-2-induced diacylglycerol (DG) kinase activation. In the present study we demonstrate IL-2-dependent activation of the alpha isoform of DG kinase. Confocal microscopy studies reveal that the enzyme is located in the cytosol and nuclei of resting T cells. Interleukin 2 stimulation induces translocation of the enzyme to the perinuclear region. Furthermore, our results indicate that inhibition of the alpha isoform of DG kinase has a profound effect on IL-2-induced T cell growth. Studies on cell cycle distribution demonstrate that the inhibition of IL-2-induced phosphatidic acid production induces arrest in late G1 phase of IL-2 dependent cells. Altogether, these results link previous observations of interleukin 2 and phosphatidic acid production to activation of an specific isoform of DG kinase and suggest that activation of this enzyme is part of a novel signaling cascade that utilizes phosphatidic acid as an effector molecule.

Cell Compartmentation↗
PubMed1997

Diacylglycerol and phosphatidate generated by phospholipases C and D, respectively, have distinct fatty acid compositions and functions. Phospholipase D-derived diacylglycerol does not activate protein kinase C in porcine aortic endothelial cells.

Stimulation of cells with certain agonists often activates both phospholipases C and D. These generate diacylglycerol and phosphatidate, respectively, although the two lipids are also apparently interconvertable through the actions of phosphatidate phosphohydrolase and diacylglycerol kinase. Diacylglycerol activates protein kinase C while one role for phosphatidate is the activation of actin stress fiber formation. Therefore, if the two lipids are interconvertable, it is theoretically possible that an uncontrolled signaling loop could arise. To address this issue structural analysis of diacylglycerol, phosphatidate, and phosphatidylbutanol (formed in the presence of butan-1-ol) from both Swiss 3T3 and porcine aortic endothelial cells was performed. This demonstrated that phospholipase C activation generates primarily polyunsaturated species while phospholipase D activation generates saturated/monounsaturated species. In the endothelial cells, where phospholipase D was activated by lysophosphatidic acid independently of phospholipase C, there was no activation of protein kinase C. Thus we propose that only polyunsaturated diacylglycerols and saturated/monounsaturated phosphatidates function as intracellular messengers and that their interconversion products are inactive.

3T3 Cells↗
PubMed1985

Biosynthetic incorporation of cis-parinaric acid into radioactive sn-3-phosphatidic acid.

Isolated guinea pig liver microsomal membranes catalyzed the incorporation of naturally occurring cis-parinaric acid into sn-3-[U-14C]glycerophosphate. This resulted in the formation of sn-3-[14C](parinaroyl)phosphatidic acid, which was isolated by Chelex-100 and DEAE-cellulose column chromatography and further purified by Sephadex-G 25. The sn-3-[14C](parinaroyl)phosphatidic acid thus obtained exhibited absorption and fluorescence spectra substantially different from the cis-parinaric acid. Distribution of the incorporated cis-parinaric acid between the hydroxyl groups of biosynthesized sn-3-[14C]phosphatidic acid was determined by degradation with Crotalus adamanteus venom. This established that the major portion of the incorporated cis-parinaric acid esterified the secondary hydroxyl group in the sn-3-[14C]phosphatidic acid, while the primary hydroxyl group was esterified to a significantly lesser degree. The similarity between the biochemical incorporation of isomeric doxyl stearic acids into lipids of biological membranes and that of cis-parinaric acid into sn-3-phosphatidic acid described in this communication are discussed in relation to the possible use of these probes in studies of intact biological membranes.

Animals↗
PubMed1960

The effects of acetylcholine on the turnover of phosphatidic acid and phosphoinositide in sympathetic ganglia, and in various parts of the central nervous system in vitro.

The effect of acetylcholine on the incorporation of P(32) into the individual phosphatides in slices of various structures of the nervous system has been studied. There was a marked stimulation of P(32) incorporation into phosphoinositide and phosphatidic acid, but not into phosphatidyl choline and phosphatidyl ethanolamine, in the cat stellate and celiac ganglia in vitro. Acetylcholine stimulated P(32) incorporation into certain phosphatides, primarily phosphoinositide and phosphatidic acid, in several structures of the cat and guinea pig brain; there was little or no effect of acetylcholine on phosphatide turnover in the inferior corpora quadrigsemina and cerebellar cortex. The suggestion is made that the phospholipid effect can best be explained as being concerned with the active transport of sodium ions out of the cell across the postsynaptic membrane of cholinergic neurons in response to acetylcholine.

Acetylcholine↗
PubMed2003

The simultaneous production of phosphatidic acid and diacylglycerol is essential for the translocation of protein kinase Cepsilon to the plasma membrane in RBL-2H3 cells.

To evaluate the role of the C2 domain in protein kinase Cepsilon (PKCepsilon) localization and activation after stimulation of the IgE receptor in RBL-2H3 cells, we used a series of mutants located in the phospholipid binding region of the enzyme. The results obtained suggest that the interaction of the C2 domain with the phospholipids in the plasma membrane is essential for anchoring the enzyme in this cellular compartment. Furthermore, the use of specific inhibitors of the different pathways that generate both diacylglycerol and phosphatidic acid has shown that the phosphatidic acid generated via phospholipase D (PLD)-dependent pathway, in addition to the diacylglycerol generated via phosphoinosite-phospholipase C (PLC), are involved in the localization of PKCepsilon in the plasma membrane. Direct stimulation of RBL-2H3 cells with very low concentrations of permeable phosphatidic acid and diacylglycerol exerted a synergistic effect on the plasma membrane localization of PKCepsilon. Moreover, the in vitro kinase assays showed that both phosphatidic acid and diacylglycerol are essential for enzyme activation. Together, these results demonstrate that phosphatidic acid is an important and essential activator of PKCepsilon through the C2 domain and locate this isoenzyme in a new scenario where it acts as a downstream target of PLD.

Animals↗
PubMed1989

Stimulatory effects of a short chain phosphatidate on superoxide anion production in guinea pig polymorphonuclear leukocytes.

Treatment of guinea pig polymorphonuclear leukocytes (PMNL) with a phosphatidate containing short-chain fatty acids, 1,2-didecanoyl-3-sn-phosphatidate (PA10), induced substantial superoxide anion (O2-) production in a dose-dependent manner, whereas phosphatidates prepared from egg lecithin and 1,2-dioleoyl-3-sn-phosphatidate (PA18:1) had no such effect. Calcium was not involved in PA10-induced O2- production, since the production was also observed in the case of addition of EGTA prior to PA10 or pretreatment of PMNL with quin-2 and EGTA to eliminate contributions of both extracellular and intracellular calcium. We have reported in previous papers that the phosphorylation of 46K protein(s), which was commonly observed in parallel with an activation of NADPH oxidase in PMNL, was increased by treatment with 10 microM 1-oleoyl-2-acetylglycerol (OAG) with little change in the O2- production (Okamura et al. (1984) Arch. Biochem. Biophys. 228, 270-277; Ohtsuka et al. (1988) Arch. Biochem. Biophys. 260, 226-231). Treatment of PMNL with a combination of PA10, which slightly increased 46K protein phosphorylation, and such a low concentration of OAG induced a marked increase in the O2- production with the increase in 46K protein phosphorylation, which was probably due to OAG action. Thus, it is likely that this protein phosphorylation plays a significant role in the stimulation of the O2- production by phosphatidate in PMNL.

Animals↗
PubMed1983

Metabolism and intracellular distribution of a fluorescent analogue of phosphatidic acid in cultured fibroblasts.

We have shown that a fluorescent compound, C6-NBD-PA, behaves as an analogue for phosphatidic acid, an important intermediate in glycerolipid biosynthesis. This derivative is preferentially transferred from phospholipid vesicles to cultured Chinese hamster fibroblasts at 2 degrees C, while the C6-NBD-PA-derived fluorescence is localized at the nuclear membrane, endoplasmic reticulum, and mitochondria. Extraction and analysis of the fluorescent lipids associated with the cells after treatment with vesicles at 2 degrees C or 37 degrees C revealed that a large fraction of the fluorescent phosphatidic acid is converted to fluorescent diglyceride, phosphatidylcholine, and triglyceride. Although we do not yet know how accurately the metabolism and intracellular distribution of C6-NBD-PA and its metabolites reflect those of endogenous phosphatidic acid, it is encouraging that this fluorescent analogue is apparently metabolized through the diglyceride pathway to give fluorescent analogues of diglyceride, triglyceride, and phosphatidylcholine. This metabolism suggests that the presence of the fluorescent group on the acyl chain of the phosphatidic acid analogue does not inhibit the enzymes involved in phosphatidic acid metabolism. We conclude that fluorescent lipid analogues such as C6-NBD-PA may be useful in correlating biochemical studies of lipid metabolism with studies of the intracellular localization of lipid metabolites by fluorescence microscopy.

4-Chloro-7-nitrobenzofurazan↗
PubMed1980

Effect of chlorpromazine administration on enzyme activity concerning phosphatidic acid metabolism in rat liver.

The effect of chlorpromazine on phospholipid metabolism was studied in rat liver endoplasmic reticulum. Administration of chlorpromazine per os caused a marked increase in microsomal phospholipid content without affecting its composition. The rate of incorporation of both [(32)P]orthophosphate and [2-(3)H)glycerol into phosphatidic acid and phosphatidylinositol increased by the administration of chlorpromazine. Enhanced labeling of phosphatidylinositol was also observed when myo-[2-(3)H]inositol was used as a precursor. The activity of glycerophosphate acyltransferase significantly increased and that of phosphatidate phosphohydrolase markedly decreased by the administration of chlorpromazine. The activity of phosphatidate cytidylyltransferase was not affected by the drug treatment. These findings suggested that the administration of chlorpromazine increases the availability of phosphatidic acid by activating glycerophosphate acyltransferase and inhibiting phosphatidate phosphohydrolase, leading to enhanced synthesis of phosphatidylinositol.

Animals↗