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PubMed1994

Characterization of phosphatidylinositol synthase and evidence of a polyphosphoinositide cycle in Plasmodium-infected erythrocytes.

Plasmodium knowlesi-infected erythrocytes possess a membranous cytidine 5'-diphospho-1,2-diacyl-sn-glycerol: myoinositol 3-phosphatidyl transferase (PI synthase) (EC 2.7.8.11) activity of 10 +/- 1.7 nmol min-1 per 10(10) infected cells. The activity was successfully solubilized with 40 mM n-octyl-beta-D-glucopyranoside in the presence of bivalent metal ions which were absolutely required for activity. The optimal pH was 8 and the apparent Ks for Mn2+ was 0.1 mM. Mg2+ allowed two-fold higher PI synthase activity, with an optimum above 100 mM. Calcium alone was ineffective while at 2 mM it inhibited solubilized PI synthase activity in the presence of 100 mM Mg2+. Enzymatic activity was fully dependent on CDP-diacylglycerol and inositol with apparent Km of 0.16 +/- 0.1 mM and 1 +/- 0.5 mM respectively. Affinity chromatography clearly showed CDP-diacylglycerol-dependent interactions of PI synthase with CDP-diacylglycerol Sepharose. However, elution of enzymatic activity in an active form was unsuccessful while SDS-PAGE of the eluate showed one apparent band. Incubations of Plasmodium falciparum-infected erythrocytes with 32P or [3H]inositol revealed de novo biosynthesis of phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate which appeared to predominate in the second half of the asexual cellular cycle. Ionomycin, a calcium ionophore, induced Li(+)-sensitive production of radioactive inositol phosphates, with neo-synthesized inositol 1,4,5-trisphosphate accumulation being the highest.

Animals↗
PubMed1992

Evidence for a role for protein kinase C in the modulation of bombesin-activated cellular signalling in human breast cancer cells.

The phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) is a potent activator of protein kinase C (PKC) and is known to affect a variety of biochemical processes in human breast cancer cells. In the present study we have employed MCF-7 cells to investigate the effects of TPA on inositol lipid signalling, the putative pathway leading to PKC activation and intracellular Ca2+ mobilization. Phosphoinositide hydrolysis in MCF-7 cells was stimulated by bombesin (BN) as evidenced by increases in both inositol phosphate production and cytidine diphosphate diacylglycerol (CDP-DG) accumulation. Pretreatment of MCF-7 cells with TPA caused attenuation of both these BN-induced responses. This inhibitory action of TPA on inositol phosphate production was mimicked by diacylglycerol analogues and was reversed by staurosporine, H-7 and tamoxifen, all known inhibitors of PKC. Furthermore, putative down-regulation of PKC by prolonged TPA pretreatment also reversed the inhibitory action of TPA and enhanced BN-induced phosphoinositide hydrolysis. TPA also inhibited BN-induced increases in cytosolic Ca2+ concentration ([Ca2+]i) and caused a dose-dependent inhibition of epidermal growth factor (EGF) binding in MCF-7 cells. However, EGF receptor occupancy was unaffected by BN. These data support an inhibitory role for PKC in the regulation of phosphoinositide hydrolysis and [Ca2+]i in breast cancer cells and provide a potential mechanism for feedback regulation of this signalling pathway in these cells.

Bombesin↗
PubMed1979

Effects of hexachlorocyclohexane isomers on concanavalin A 'capping' in bovine lymphocytes.

The effects of alpha, beta, gamma, and delta isomers of hexachlorocyclohexane on concanavalin A 'capping' in bovine lymphocytes were evaluated, gamma and delta hexochlorocyclohexane inhibited 'capping' whereas the alpha and beta isomers were without effect. In addition, gamma-hexachlorocyclohexane has been shown to antagonize the maintenance of preformed 'caps' and cause the rapid dispersal of the concanavalin A-receptor complexes over the surface of cells by a temperature-dependent mechanism. The possible role of a gamma-hexachlorocyclohexane-sensitive process in the organization of microflow patterns in the lectin-activated lymphocyte membrane is discussed.

Animals↗
PubMed1990

Lithium potentiates agonist formation of [3H]CDP-diacylglycerol in human platelets.

Thrombin stimulated a rapid formation of [3H]CDP-diacylglycerol in platelets prelabelled with [3H]cytidine. This response was increased in the presence of LiCl after a delay of 5 min; potentiation could be prevented by myo-inositol. Since Li+ inhibits the liberation of inositol from inositol phosphates, the conversion of diacylglycerol to phosphatidylinositol via CDP-diacylglycerol may be dependent on the regeneration of inositol from this pathway.

Blood Platelets↗
PubMed2004

Peripheral inflammation increases phosphoinositide activity in the rat dorsal horn.

Persistent pain leads to changes in the spinal cord that contribute to hyperalgesia and allodynia. The effort to characterize these changes has focused on neurotransmitters and receptors, while relatively little is known about pain-associated modulation of second-messenger responses. Nearly all neurotransmitters can activate the phosphoinositide (PI) second-messenger system which has been investigated using a method that localizes membrane-bound [(3)H]CDP-diacylglycerol (DAG) produced from the precursor [(3)H]cytidine [Science 249 (1990) 802]. The present study applied this method in spinal cord slices from rats injected with complete Freund's adjuvant in one hindpaw and from uninflamed control rats. Two days after the injection, slices were removed and maintained in vitro for pharmacological testing. Some slices were exposed to the acetylcholine agonist carbachol which is antinociceptive in the spinal cord. Inflammation resulted in increased baseline, unstimulated [(3)H]CDP-DAG accumulation, especially in superficial dorsal horn layers, as well as enhanced carbachol-stimulated labeling. These results suggest that persistent pain leads to neurochemical changes within the spinal cord that could potentially enhance responses to a spectrum of pain-modulating transmitters.

Animals↗
PubMed2006

Identification and characterization of human cardiolipin synthase.

The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase. In this study, we identified a human candidate gene/cDNA for cardiolipin synthase, C20orf155. Expression of this candidate cDNA in the (cardiolipin synthase-deficient) crd1Delta yeast confirmed that it indeed encodes human cardiolipin synthase. Purified mitochondria of the crd1Delta expressing human cardiolipin synthase were used to characterize the enzyme. It has an alkaline pH optimum, requires divalent cations for activity and appears to have a different substrate preference for cytidinediphosphate-diacylglycerol species when compared to phosphatidylglycerol species. The possible implications for CL synthesis and remodeling are discussed.

Cardiolipins↗
PubMed2005

Regulation of gene expression by lithium and depletion of inositol in slices of adult rat cortex.

Lithium inhibits inositol monophosphatase at therapeutically effective concentrations, and it has been hypothesized that depletion of brain inositol levels is an important chemical alteration for lithium's therapeutic efficacy in bipolar disorder. We have employed adult rat cortical slices as a model to investigate the gene regulatory consequences of inositol depletion effected by lithium using cytidine diphosphoryl-diacylglycerol as a functionally relevant biochemical marker to define treatment conditions. Genes coding for the neuropeptide hormone pituitary adenylate cyclase activating polypeptide (PACAP) and the enzyme that processes PACAP's precursor to the mature form, peptidylglycine alpha-amidating monooxygenase, were upregulated by inositol depletion. Previous work has shown that PACAP can increase tyrosine hydroxylase (TH) activity and dopamine release, and we found that the gene for GTP cyclohydrolase, which effectively regulates TH through synthesis of tetrahydrobiopterin, was also upregulated by inositol depletion. We propose that modulation of brain PACAP signaling might represent a new opportunity in the treatment of bipolar disorder.

Animals↗
PubMed1986

Differences in phospholipid incorporation of 32P relevant to alpha 1-receptor coupling events in rat and rabbit aorta.

Labelling of membrane phospholipids with 32P was compared in rat and rabbit aorta under basal conditions and during alpha 1-receptor stimulation. Incorporation of 32P proceeded at a significantly higher rate in rat tissue. The ratio of basal labelling following 30 min of incubation for rat/rabbit arteries was 4.8 for phosphatidylinositol diphosphate (PIP2), 6.0 for phosphatidylinositol phosphate (PIP), 9.0 for phosphatidylinositol (PI), 6.0 for phosphatidic acid (PA) and 18.7 for phosphatidylcholine (PC). Addition of 10(-5)M norepinephrine (NE) to labelled tissues resulted in a similar decrease in [32P]-PIP2 in both rat and rabbit tissues. Greater percent increases were seen in rabbit tissue of [32P]-PA (4-6 fold), and [32P]-PI (3-5 fold), when measured over the initial 10 minutes of agonist exposure. While NE caused a gradual increase of 32P incorporation into PC in rabbit aorta, reaching 180% above control after 10 minutes, PC labelling was not increased in rat aorta. Our findings provide evidence for the enhanced labelling of rat vs rabbit aorta phospholipids. This may account for differences in receptor responses and associated Ca+ movements which have been previously recognized to exist between aorta of these two species.

Animals↗
PubMed1999

Relationship between dopamine agonist stimulation of inositol phosphate formation and cytidine diphosphate-diacylglycerol accumulation in brain slices.

Dopamine receptor-coupled stimulation of inositol phosphate formation has been characterized extensively, but little is known about the diacylglycerol arm of this dual-signaling pathway. This study examined several parameters of cytidine diphosphate-diacylglycerol (CDP-DG) accumulation as an index of agonist-stimulated DG formation. Rat brain slices pre-labeled with 5-[3H]cytidine were incubated with various test agents in the presence of LiCl and accumulated CDP-DG analyzed. Dopamine and SKF38393 significantly and dose-dependently stimulated CDP-DG accumulation. SKF38393 responses were inhibited by neomycin and reversed by myo-inositol or by exclusion of LiCl. Compared to inositol phosphate formation in 2-[3H]inositol-prelabeled slices, the CDP-DG responses were proportionately greater, while the agonist EC50 values were similar between the two assays. The D1-receptor antagonist SCH23390 inhibited SKF38393-mediated responses at 0.1-10 microM concentrations, whereas greater concentrations reversed the inhibition. SKF38393 effects were completely blocked by the DG kinase inhibitor R59022, thus precluding any role for phospholipase-D or de novo phosphatidate synthesis in the dopaminergic response. D609 which inhibits phosphatidylcholine-specific phospholipase-C (PLC), potently inhibited both CDP-DG accumulation and inositol phosphate formation. These findings demonstrate that the selective D1-receptor antagonist SCH23390 is a partial agonist at the D1-like dopamine receptor that couples to phosphoinositide signaling, that dopaminergic facilitation of phosphoinositide signaling is independent of de novo phosphatidate synthesis, and that the widely used enzyme inhibitor, D-609, is probably not selective for phosphatidylcholine-specific PLC in brain slice preparations. The greater sensitivity of the CDP-DG measurement presents this assay as a reliable and possibly superior index of dopamine receptor-coupled PLC activation in intact tissues.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Phosphatidylglycerophosphate synthases from Arabidopsis thaliana.

Two Arabidopsis thaliana genes were shown to encode phosphatidylglycerophosphate synthases (PGPS) of 25.4 and 32.2 kDa, respectively. Apart from their N-terminal regions, the two proteins exhibit high sequence similarity. Functional expression studies in yeast provided evidence that the 25.4 kDa protein is a microsomal PGPS while the 32.2 kDa protein represents a preprotein which can be imported into yeast mitochondria and processed to a mature PGPS. The two isozymes were solubilized and purified as fusion proteins carrying a His tag at their C-terminus. Enzyme assays with both membrane fractions and purified enzyme fractions revealed that the two A. thaliana isozymes have similar properties but differ in their CDP-diacylglycerol species specificity.

Arabidopsis↗
PubMed2001

SKF83959 exhibits biochemical agonism by stimulating [(35)S]GTP gamma S binding and phosphoinositide hydrolysis in rat and monkey brain.

SKF83959, a benzazepine with high affinity for aminergic receptors, elicits behaviors such as grooming and vacuous chewing that are characteristic of dopamine D(1)-like receptor stimulation in rodents. Unlike classical D(1) agonists, however, SKF83959 does not stimulate adenylyl cyclase. Knowing that some D(1)-like receptors are coupled to phospholipase C-mediated signaling cascades in the brain, the present study aimed to determine whether SKF83959 exhibits an agonistic action at the biochemical level and also whether this benzazepine can modulate phosphoinositide hydrolysis in a manner that would be consistent with the behavioral effects of the drug. Similar to dopamine and the selective D(1)-like agonist SKF38393, SKF83959 competitively displaced the receptor binding of [(3)H]dopamine in an agonist-like manner, significantly stimulated [(35)S]guanosine-5'-O-(3-thio)triphosphate binding, and potently enhanced phospholipase C-mediated phosphoinositide hydrolysis in rat and monkey brain tissues. SKF83959 was generally more potent than SKF38393, whereas SKF38393 consistently exhibited greater pharmacological efficacy. These findings may implicate a role for the phospholipase C signaling cascade in the agonistic behavioral and antiparkinsonian activity of SKF83959. Dopamine-sensitive phospholipase C signaling should probably be considered in subsequent formulations of mechanisms and models of dopaminergic function in the normal or diseased brain.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMedDate not supplied

Phospholipid biosynthesis in the yeast Saccharomyces cerevisiae and interrelationship with other metabolic processes.

In this review, we have discussed recent progress in the study of the regulation that controls phospholipid metabolism in S. cerevisiae. This regulation occurs on multiple levels and is tightly integrated with a large number of other cellular processes and related metabolic and signal transduction pathways. Progress in deciphering this complex regulation has been very rapid in the last few years, aided by the availability of the sequence of the entire Saccharomyces genome. The assignment of functions to the remaining unassigned open reading frames, as well as ascertainment of remaining gene-enzyme relationships in phospholipid biosynthesis in yeast, promises to provide detailed understanding of the genetic regulation of a crucial area of metabolism in a key eukaryotic model system. Since the processes of lipid metabolism, secretion, and signal transduction show fundamental similarities in all eukaryotes, the dissection of this regulation in yeast promises to have wide application to our understanding of metabolic control in all eukaryotes.

CDPdiacylglycerol-Serine O-Phosphatidyltransferase↗
PubMed1996

Regulation of phosphatidate phosphatase activity from the yeast Saccharomyces cerevisiae by phospholipids.

Regulation of Saccharomyces cerevisiae membrane-associated phosphatidate phosphatase (3-sn-phosphatidate phosphohydrolase, EC 3.1.3.4) activity by phospholipids was examined using purified enzyme and Triton X-100/phospholipid-mixed micelles. Anionic phospholipids activated phosphatidate phosphatase activity whereas zwitterionic phospholipids had a slight inhibitory effect on activity. Cardiolipin (A0.5 = 1.9 mol %), CDP-diacylglycerol (A0.5 = 2.6 mol %), and phosphatidylinositol (A0.5 = 5.5 mol %) were the most potent anionic phospholipid activators. Enzyme activation by cardiolipin (n=2.8), CDP-diacylglycerol (n=2.1), and phosphatidylinositol (n=3.3) followed positive cooperative kinetics. A kinetic analysis was performed to determine the mechanism of phosphatidate phosphatase activation by anionic phospholipids. The dependence of phosphatidate phosphatase on phosphatidate was cooperative (n approximately 2.2) in the absence and presence of phospholipid activators. Cardiolipin, CDP-diacylglycerol, and phosphatidylinositol were mixed competitive activators of phosphatidate phosphatase activity. The major effect of the activators was to cause a decrease in the Km for phosphatidate. Sphinganine, a positively charged sphingoid base, inhibited phosphatidate phosphatase activity and antagonized the activation of the enzyme by cardiolipin and phosphatidylinositol. Sphinganine caused an increase in the cooperativity of cardiolipin activation, but had little effect on the A0.5 value for cardiolipin. On the other hand, sphinganine had little effect on the cooperativity of phosphatidylinositol activation, but caused an increase in the A0.5 value for phosphatidylinositol. The activation constants for cardiolipin, CDP-diacylglycerol, and phosphatidylinositol were within the range of their cellular concentrations. These results suggested that the activation of phosphatidate phosphatase activity by anionic phospholipids may be physiologically relevant.

Cardiolipins↗
PubMed1977

Factors controlling the activities of phosphatidate phosphohydrolase and phosphatidate cytidylyltransferase. The effects of chlorpromazine, demethylimipramine, cinchocaine, norfenfluramine, mepyramine and magnesium ions.

1. Microsomal membranes from rat liver were incubated with ATP, CoA, Mg2+, [14C]palmitate, F- and sn-glycerol 3-phosphate in order to label them with [14C]phosphatidate. These membranes were isolated and used in a second incubation in which [3H]CTP was present, and the simultaneous synthesis of [14C]diacylglycerol and [3H]CDP-diacylglycerol was measured. 2. The addition of phosphatidate phosphohydrolase, which had been partially purified from the particle-free supernatant, supplemented the activity of the endogenous phosphohydrolase, but it did not alter the rate of CDP-diacylglycerol formation. 3. Adding EDTA inhibited phosphatidate cytidylyl-transferase activity and stimulated the activity of the phosphohydrolases by removing excess of Mg2+. 4. Increasing the concentration of Mg2+, norfenfluramine or chlorpromazine in the assay system stimulated cytidylyltransferase activity, but decreased the activities of both phosphohydrolases. 5. The mechanism for the stimulation of cytidylyl=transferase activity by the cationic drugs and Mg2+ was investigated with emulsions of phosphatidate and the microsomal fraction of rat liver. 6. There was a threshold concentration of about 5mM-MgCl2 below which no cytidylyltransferase activity was detected in the presence or absence of norfenfluramine. Just above this threshold concentration norfenfluramine stimulated cytidylyltransferase activity, but this stimulation disappeared as the Mg2+ concentration was raised to its optimum of 20mM. Norfenfluramine therefore partially replaced the bivalent-cation requirement. 7. At 30 mM-MgCl2 amphiphilic cationic drugs inhibited cytidylyltransferase activity at relatively high concentrations in a non-competitive manner with respect to phosphatidate. 8. The implications of these results are discussed with respect to the regulation of the synthesis of the acidic phospholipids compared with the synthesis of phosphatidylcholine, phosphatidylethanolamine and triacylglycerol.

Animals↗
PubMed1980

Subcellular distribution and some properties of N-ethylmaleimide-sensitive and-insensitive forms of glycerol phosphate acyltransferase in rat adipocytes.

1. Glycerol phosphate acyltransferase (GPAT) activities were measured in subcellular fractions obtained from rat epididymal adipocytes. These contained both N-ethylmaleimide-sensitive and N-ethylmaleimide-insensitive forms of the enzyme. 2. As shown by parallel measurements of marker enzymes, N-ethylmaleimide-insensitive GPAT is most probably a mitochondrial activity, whereas N-ethylmaleimide-sensitive GPAT is the microsomal enzyme. 3. Subcellular distributions are also reported for dihydroxyacetone phosphate acyltransferase (DHAPAT) (assayed with and without N-ethylmaleimide), monoacylglycerol phosphate acyltransferase (MGPAT) and Mg2+-dependent and Mg2+-independent forms of phosphatidate phosphohydrolase (PPH).

1-Acylglycerol-3-Phosphate O-Acyltransferase↗
PubMed1983

The bivalent-cation dependence of phosphatidylinositol synthesis in a cell-free system from lymphocytes.

The bivalent-cation requirements of two enzymes involved in phosphatidylinositol synthesis were defined for pig lymphocyte membranes using a citric acid buffer. CTP:phosphatidic acid cytidylyltransferase (EC 2.7.7.41) is activated by free Mn2+ concentrations above 20nM and by free Mg2+ concentrations above 10 microM. When activated by Mg2+, the enzyme is weakly inhibited by Ca2+ (Ki greater than 250 microM), but Ca2+ has no effect when Mn2+ is used to stimulate CDP-diacylglycerol synthesis. The synthesis of phosphatidylinositol from phosphatidic acid is also stimulated by Mn2+ and Mg2+ concentrations similar to those above and is inhibited by free Ca2+ concentrations above 500nM, probably by its action on CDP-diacylglycerol:inositol 3-phosphatidyltransferase (EC 2.7.8.11). Taken together, these studies suggest that under physiological conditions phosphatidylinositol synthesis is activated by Mg2+ and it is possible that it is further regulated by the free concentrations of Ca2+ and/or Mn2+.

Animals↗
PubMed1989

Potentiation by lithium of CMP-phosphatidate formation in carbachol-stimulated rat cerebral-cortical slices and its reversal by myo-inositol.

This paper describes a rapid and simple method for measuring CMP-phosphatidate (CMP-PA; CDP-diacylglycerol), providing a novel assay for inositol phospholipid metabolism. Rat cerebral-cortical slices labelled with [14C]cytidine were incubated with the muscarinic cholinergic agonist carbachol in the presence of various concentrations of LiCl; 10 mM-LiCl greatly enhanced the carbachol-stimulated formation of [14C]CMP-PA over a 60 min incubation period. The potentiation by Li+ was concentration-dependent, with a maximal enhancement at 3 mM and half-maximal enhancement at 0.6 mM-LiCl. The enhancement by Li+ could be reversed by incubation with myo-inositol; a maximal effect was observed with 10 mM-inositol. A similar, though smaller, enhancement of CMP-PA concentrations in the presence of LiCl was observed in slices stimulated with noradrenaline, 5-hydroxytryptamine and K+. The results are discussed in relation to previously observed effects of Li+ on inositol phospholipid metabolism.

Animals↗