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PubMed2004

Phosphoinositide involvement in phagocytosis and phagosome maturation.

Cells of the innate immune system engulf invading microorganisms into plasma membrane-derived vacuoles called phagosomes. Newly formed phagosomes gradually acquire microbicidal properties by a maturation process which involves sequential and coordinated rounds of fusion with endomembranes and concomitant fission. Some pathogens interfere with this maturation sequence and thereby evade killing by the immune cells, managing to survive intracellularly as parasites. Phosphoinositides seem to be intimately involved in the processes of phagosome formation and maturation, and initial observations suggest that the ability of some microorganisms to survive intracellularly is associated with alterations in phosphoinositide metabolism. This chapter presents a brief overview of phosphoinositides in cells of the immune system, their metabolism in the context of phagocytosis and phagosome maturation and their possible derangements during infectious pathogenosis.

Animals↗

PubMed2004

Nuclear phosphoinositides and their functions.

Phosphoinositides are minor components of biological membranes, which have emerged as essential regulators of a variety of cellular processes, both on the plasma membrane and on several intracellular organelles. The versatility of these lipids stems from their ability to function either as substrates for the generation of second messengers, as membrane-anchoring sites for cytosolic proteins or as regulators of the actin cytoskeleton. Despite a vast literature demonstrating the presence of phosphoinositides in the nucleus, only recently has the function(s) of the nuclear pool of these lipids and their soluble analogues, inositol polyphosphates, started to emerge. These compounds have been shown to serve as essential co-factors for several nuclear processes, including DNA repair, transcription regulation and RNA dynamics. In this light, phosphoinositides and inositol polyphosphates might represent high turnover activity switches for nuclear complexes responsible for these processes. The regulation of these large machineries would be linked to the phosphorylation state of the inositol ring and limited temporally and spatially based on the synthesis and degradation of these molecules.

Active Transport, Cell Nucleus↗

PubMed1989

Second messengers involved in the muscarinic control of the heart: the role of the phosphoinositide response.

Two heart muscarinic responses are compared, the reduction of cyclic AMP concentration and the hydrolysis of phosphoinositides. It is suggested that the former is more important physiologically, since the latter is a slow response requiring much higher agonist concentrations. Inositol trisphosphate released from phosphoinositides is unlikely to produce a positive inotropic effect by releasing calcium from the sarcoplasmic reticulum. However, long term muscarinic effects may involve activation of protein kinase C by diacylglycerol released from phosphoinositides.

Animals↗

PubMed1992

Alterations of choline acetyltransferase, phosphoinositide hydrolysis, and cytoskeletal proteins in rat brain in response to colchicine administration.

Colchicine, a microtubule disrupting toxin, was administered intracerebroventricularly to rats, followed by measurements of (i) the activity of choline acetyltransferase, a biochemical marker of cholinergic neurons, (ii) cytoskeletal protein concentrations, including tau, MAP-2, spectrin, and tubulin, and (iii) the activity of the second messenger-generating system, receptor-coupled phosphoinositide hydrolysis. One week after colchicine treatment there was a 60% decrease in choline acetyltransferase activity in the hippocampus, which was followed by a gradual increase in only a 29% deficit after 12 weeks. In the striatum and cerebral cortex, choline acetyltransferase activity was slightly reduced (by 13% and 19%, respectively) 1 week after colchicine treatment followed by increases to control values. The concentrations of tau and tubulin in the hippocampus were unaltered by colchicine treatment, and MAP-2 and spectrin were only slightly reduced 4 weeks after colchicine. Hippocampal phosphoinositide hydrolysis induced by norepinephrine was elevated approximately 28% 1 and 2 weeks after colchicine treatment and that induced by ibotenate was increased by 53% 2 weeks after colchicine. These results demonstrate that colchicine causes a severe depletion of choline acetyltransferase 1 week after administration. There was not a significant reduction of the concentration of any of the cytoskeletal proteins after 1 week, possibly due to the cell-selectivity of the toxic effect of colchicine, but there was a delayed, and temporary, decline of MAP-2 and spectrin concentrations. Associated with the decreased choline acetyltransferase activity after 1 week was an enhanced phosphoinositide hydrolysis in response to norepinephrine, and after 2 weeks there were enhanced responses to norepinephrine and to ibotenate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Substance P action on phosphoinositides in guinea-pig intestinal muscle: a possible transduction mechanism?

The effect of substance P on the metabolism of membrane phosphoinositides and the possible role of this effect in the contractile response to substance P was investigated in longitudinal muscle strips obtained from the guinea-pig small intestine and prelabelled with [3H] inositol. Substance P (2.2 microM) failed to change significantly the tissue content of phosphoinositides but caused an accumulation of their water-soluble hydrolysis products, inositol bisphosphate (InsP2) and inositol monophosphate (InsP). These experiments were carried out in the presence of Li+ (12 mM), since only under these conditions could an accumulation of InsP2 be observed. The rate at which InsP2 and InsP accumulated was highest during the first 0.5 min of exposure to substance P (2.2 microM) and then decreased rapidly. Thus, the rate of inositol phosphate accumulation paralleled the time course of the contractile response to substance P. The magnitude of inositol phosphate accumulation was related to the concentration of substance P (22 nM-22 microM). The substance P-induced accumulation of InsP2 and InsP was not reduced when muscle strips had been incubated in Ca2+-free medium, for a time period sufficient to deplete the intracellular Ca2+ store which can be released by substance P, or in Ca2+-free medium containing high [K+]. These findings are compatible with the concept that hydrolysis of membrane phosphoinositides is a mechanism that links substance P receptor activation to contraction but further work is needed to establish a causal relationship.

Animals↗

PubMedDate not supplied

Changes in phosphoinositide-specific phospholipase C and phospholipase A2 activity in ischemic and reperfused rat heart.

Phospholipid metabolism is altered during ischemia and post-ischemic reperfusion. Past studies demonstrating elevated myocardial free fatty acid and lysophospholipid content infer accelerated phospholipid degradation involving phospholipase A activity. Recently, ischemic and post-ischemic reperfusion (reperfusion) have been shown to affect levels of phosphoinositide (PPI) degradation products. Considering the role of PPI turnover in regulation of cellular calcium homeostasis, our laboratory and others have suggested that alteration in the metabolism of the inositol phospholipids could play a role in the development of ischemia-induced calcium overload injury. Using an isolated rat heart model (Langendorff perfusion), this study examines the effect of global ischemia and reperfusion on ventricular phosphoinositide-specific phospholipase C (PLC) activity and PLA2 activity. The primary purpose was to determine if ischemia and reperfusion-induced changes in PLC activity could explain previously observed changes in PPI degradation products, and whether PLC and PLA2 activities were similarly or differentially altered by ischemia and reperfusion. PLC and PLA2 activities were measured in cytosolic and total membrane fractions from control (perfused), ischemic (5, 10, 30, and 60 min), and post-ischemic reperfused ventricular tissue. Phospholipase activity was determined under optimal in vitro conditions using exogenous radiolabeled substrates. Alterations in membrane-associated PPI-PLC activity correlated with reported ischemia and reperfusion-induced changes in ventricular content of PPI metabolites. Membrane PLC activity increased slightly at 5 min of ischemia, decreased significantly at 10 min of ischemia, and continued to decrease with longer duration of ischemia (73% of control after 60 min). Cytosolic PPI-PLC activity was decreased at 5 min, and then significantly increased by longer durations of ischemia, while cytosolic PLA2 activity was reduced at all time points. Pretreatment with muscarinic, alpha 1-adrenergic, beta-adrenergic, and adenosine receptor blockers did not alter ischemia-elicited changes in PLC activity. Reperfusion caused a 140% to 200% rise in the activities of all phospholipases in all fractions after 40 min of ischemia, but not after 10 min of ischemia. Results suggest 1) ischemia and reperfusion-elicited alterations in membrane-associated PPI-PLC activity can explain previously observed changes in phosphoinositide turnover metabolites, 2) cytosolic and membrane-associated PPI-PLC and PLA2 activities are not uniformly affected by ischemia, 3) reperfusion following ischemia of sufficient duration initiates uniform activation of PIP2-PLC and PLA2, and 4) because ischemia and reperfusion-induced changes in phospholipase activity can be detected under optimal in vitro assay conditions (removed from the in vivo ischemic microenvironment), it is likely that the enzymes themselves have been altered.

Animals↗

PubMed1991

Time-, concentration-, and age-dependent inhibition of muscarinic receptor-stimulated phosphoinositide metabolism by ethanol in the developing rat brain.

We have previously reported that administration of ethanol (EtOH; 4 g/Kg/day) to rats from postnatal day 4 to day 10 causes microencephaly and decreases muscarinic receptor-stimulated inositol metabolism on days 7 and 10. An identical exposure to EtOH of adult rats, which resulted in similar blood EtOH concentrations, did not have any effect on the same system. Initial in vitro studies have shown the presence of a differential sensitivity to EtOH of the phosphoinositide system coupled to muscarinic receptors during development. In the present study we have expanded these findings by investigating the concentration-, time-, and age-dependent effects of EtOH on accumulation of [3H]inositol phosphates ([3H]InsPs) in brain slices. EtOH caused a dose-dependent inhibition of carbachol-stimulated phosphoinositide metabolism in cerebral cortex slices from 7 day-old rats. When the time of incubation with EtOH was increased to 90 minutes, concentrations as low as 50 mM, which are reached following in vivo administration of EtOH, significantly inhibited the muscarinic response. The effect of EtOH was rather specific for the muscarinic receptors, since, even with longer incubation times, the accumulation of [3H]InsPs induced by norepinephrine or serotonin was inhibited only at concentrations of 150-500 mM. The effect of EtOH was more pronounced in cerebral cortex, hippocampus and cerebellum, and less in the brainstem. The potency of EtOH in inhibiting carbachol-stimulated phosphoinositide metabolism was also dependent on the age of the animals. Its effect was maximal in the 7-day-old rat and less pronounced in younger and older animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1988

Defective phosphoinositide metabolism in primary hypertension.

An increase in free cytosolic calcium content has been reported in essential hypertension. Since within the membrane, the phosphoinositides participate in the control of cell calcium homeostasis, we investigated whether impaired phosphoinositide metabolism could account for the calcium handling abnormality observed in hypertensives. In erythrocyte membranes of hypertensives the activity of kinases involved in polyphosphoinositide formation appears to be impaired and could be related to the alteration in calcium handling binding capacity and ATP-dependent calcium transport. In platelets of hypertensives, the hyperactivity of phospholipase C (observed even in the absence of calcium in the external medium) is likely to be responsible for the hypersensitivity of cells to various agonists. These observations are consistent with the hypothesis that in cells from hypertensives, a membrane defect linked to phosphoinositide metabolism is involved in the overall calcium handling defect.

Animals↗

PubMed1999

Amyloid beta peptide 25-35 modulates hydrolysis of phosphoinositides by membrane phospholipase(s) C of adult brain cortex.

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C. Cholinergic pathways are important in learning and memory, and deficits in cholinergic transmission have been implicated in Alzheimer's disease (AD). AD is also associated with increased beta-amyloid plaques. In the present study, we have investigated the effect of the amyloid beta (A beta) synthetic peptide homologous to residue 25-35 of A beta in nonaggregated and aggregated forms on the degradation of inositol phospholipids. Synaptic plasma membranes (SPM) and the cytosolic fraction from rat brain cortex served as a source of enzymes. The studies were carried out with radioactive inositol phospholipids in the presence of endogenous and 2 mM CaCl2. The enzyme(s) activity was evaluated by determination of the product formation of [3H]inositol-1-phosphate (IP1) or [3H]inositol-1,4,5-trisphosphate (IP3). Results show that the PI-PLC activity was significantly higher in cytosol compared to SPM, and this enzyme was stimulated by 2 mM CaCl2, but not by GTPgammaS or carbachol, a cholinergic receptor agonist. Activity of the SPM-bound PIP2-PLC was similar to that in cytosol and was not activated by 2 mM CaCl2. The SPM PIP2-PLC was significantly stimulated by GTPgammaS together with the cholinergic agonist, carbachol. Fresh-water-soluble A beta 25-35 activated PI-PLC in SPM markedly by two- to threefold, but this effect was absent in the presence of 2 mM CaCl2. Moreover, A beta 25-35 had no effect on basal PIP2-PLC activity and cytosolic PI-PLC and PIP2-PLC. The aggregated form of A beta 25-35 significantly inhibited PIP2-PLC only in the presence of endogenous CaCl2. It also inhibited the carbachol and GTP(gamma)S-stimulated PIP2-PLC. Our findings show that depending on the aggregation state and Ca2+ concentration, A beta modulates phosphoinositide degradation differently and exclusively in brain synaptic plasma membranes. Our data suggested that aggregated A beta peptide may be responsible for the significant impairment of phosphoinositide signaling found in brain membranes during AD.

Age Factors↗

PubMed1990

Platelet activity and phosphoinositide turnover increase with advancing age.

PURPOSE: Blood platelet activity increases with advancing age. This study was designed to determine if changes in a key signal-transducing mechanism in the platelet, phosphoinositide turnover, are associated with the enhanced platelet activity seen in aging. PATIENTS AND METHODS: Platelets were harvested from a total of 40 healthy, non-obese, 22- to 62-year-old individuals, free of any clinical evidence of atherosclerotic vascular disease, and having normal serum laboratory lipid levels. Studies of platelet activity included measurement of in vitro platelet aggregation and plasma beta-thromboglobulin (beta-TBG), a marker of in vivo platelet secretion. Basal and thrombin-stimulated phosphoinositide turnover was measured following [32P]-orthophosphate incorporation into the various phospholipids, isolation of the phosphoinositides and phosphatidic acid by thin-layer chromatography and autoradiography, and quantification by liquid scintillation spectroscopy of these radiolabeled phospholipids. RESULTS: There was a positive correlation with age for both adenosine diphosphate (ADP)-induced aggregation (1.25 microM, r = 0.464, p less than 0.001; 2.5 microM, r = 0.386, p less than 0.05) and plasma beta-TBG (r = 0.381, p less than 0.055). There was a time-dependent increase of [32P]orthophosphate (32Pi) incorporation into platelet phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 4-phosphate (PIP), and isotopic equilibrium was reached by 120 minutes at 37 degrees C. A positive correlation was found between age and basal 32P-PIP2 (r = 0.640, p less than 0.001) and 32P-PIP (r = 0.676, p less than 0.0005). Basal 32Pi incorporation into PIP2 correlated positively with in vitro aggregation (1.25 microM ADP, r = 0.795, p less than 0.0001; 2.5 microM ADP, r = 0.755, p less than 0.0005) as did 32Pi incorporation into PIP (1.25 microM ADP, r = 0.815, p less than 0.0001; 2.5 microM ADP, r = 0.795, p less than 0.0001). There was also a positive correlation between plasma beta-TBG levels and basal 32P-PIP2 (r = 0.768, p less than 0.005) and 32P-PIP (r = 0.505, p less than 0.066). Finally, increasing age correlated with thrombin (4 U/mL)-stimulated 32P-PIP2 hydrolysis (r = 0.694, p less than 0.01) and phosphatidic acid formation (r = 0.556, p less than 0.05).

Adenosine Diphosphate↗

PubMed1988

Altered phosphoinositide fatty acid composition, mass and metabolism in brain essential fatty acid deficiency.

This study describes the specific alterations in phosphoinositide mass and fatty acid composition observed in brain essential fatty acid deficiency (EFAD). These investigations were motivated by the observation that alterations in volatile anesthetic potency were associated with changes in brain arachidonyl-phosphatidylinositol (PI) content, and were aimed at defining whether EFAD might alter the generation of chemical second messengers via the PI cycle. Analyses of cerebral cortical phosphoinositide mass and fatty acid composition showed that EFAD results in specific and preferential depletion of arachidonate (20:4(n - 6); 5,8,11,14-eicosatetraenoic acid) from cerebral cortical polyphosphoinositides, and that this depletion is reversed by parenteral supplementation with linoleic acid (18:2(n - 6); 9,12-octadecadienoic acid). These analyses also showed that, while phosphoinositides containing 20:3(n - 9) (5,8,11-eicosatrienoic acid) accumulated in EFAD, linoleate supplementation decreased 20:3(n - 9)-PI and 20:3(n - 9)-phosphatidylinositol 4-phosphate (PIP), but resulted in accumulation of 20:3(n - 9)-phosphatidylinositol 4,5-bisphosphate (PIP2). Comparison of the fatty acid composition of brain polyphosphoinositides and 1,2-diacylglycerols between treatment groups showed that diacylglycerols contain a lower molar percentage of 20:3(n - 9) and a higher percentage of arachidonate than the corresponding polyphosphoinositides. The combined results of these studies suggest the existence of fatty acid substrate specificity for the hydrolysis of PIP2 by phospholipase C. The biological relevance of these findings is suggested by a strong correlation between the mass of cerebral cortical arachidonyl-PIP2 and the potency of the anesthetic halothane.

Animals↗

PubMed1985

Phosphoinositides are not phosphorylated by the very active tyrosine protein kinase from the murine lymphoma LSTRA.

We studied the ability to phosphorylate phosphoinositides by 3 different subcellular preparations, and immunopurified tyrosine protein kinase (TPK) from two murine lymphoma cell lines induced by the Moloney murine leukemia virus: LSTRA with a very active TPK and MBL2 without significant TPK activity. We could not find any difference in the phosphorylation of phosphoinositides by these preparations. The TPK purified with two antibodies which phosphorylate actively tyrosine on exogenous substrate were unable to phosphorylate phosphoinositides.

Animals↗

PubMed1986

Covalent linkage of phosphoinositides to myelin basic protein: in vivo occurrence and in vitro studies with experimental allergic encephalomyelitis.

We have previously reported the covalent attachment of phosphoinositides to myelin basic protein (MBP) in vitro. In this study, in vivo phosphoinositidation of MBP was observed to occur after intracerebral injection with [32p]HPO4(2-). In the in vitro study of experimental allergic encephalomyelitis, a four-fold increase in phosphoinositidation of MBP was observed in the myelin from the guinea pigs sacrificed during the development of motor dysfunction, as compared to the control group. A decrease (40%) was observed among most of the animals sacrificed before the onset of motor dysfunction.

Adenosine Triphosphate↗

PubMed1987

Effect of a collagen-derived octapeptide on phosphoinositide turnover and 43K protein phosphorylation in collagen-activated platelets.

A collagen-derived octapeptide KPGEPGPK which specifically inhibits the activation of platelets by collagen has been tested for its ability to affect the collagen-induced phosphoinositide breakdown and protein phosphorylations. Collagen produced a transient decrease followed by a rapid resynthesis of [32P]-phosphatidyl 4-5 bisphosphate (PIP2) and 4-mono phosphate (PIP). Octapeptide, at a concentration preventing aggregation but allowing shape change, did not impair the phosphoinositide breakdown, whereas the P43 phosphorylation was strongly inhibited. Higher concentrations of peptide which did not permit any shape change were needed to hinder the PIP2 and PIP decrease. Therefore, the octapeptide appears to affect early events of the collagen-induced platelet activation involving the P43 phosphorylation, independently of its effect on the receptor-stimulated phosphoinositide hydrolysis.

Blood Platelets↗

PubMed1987

Functional and biochemical interaction of dibutyryl cyclic AMP with the phosphoinositide system in isolated rat parietal cells.

The interaction of the muscarinic agonist carbachol and of dibutyryl cAMP on acid secretion and phosphoinositide second messenger metabolism were studied in rat gastric parietal cells. Compared to the added effects of each agonist alone aminopyrine uptake, a measure of acid secretion, was enhanced 2-4-fold by the combination of both compounds. In addition the ED50 for carbachol was left shifted in the presence of dibutyryl-cAMP. The cholinergic stimulation of inositol phosphate production was slightly inhibited by dibutyryl-cAMP while levels of diacylglycerol were not affected. Thus the interaction of the cAMP and the phosphoinositide systems involve potentiation and positive sensitivity modulation of the cholinergic response by cAMP which is mediated by events distal to the generation of phosphoinositide second messengers.

Aminopyrine↗

PubMed1988

Periodic acid-induced blastogenesis of lymphocytes is independent of phosphoinositide turnover.

The blastogenic transformation of lymphocytes by periodic acid was investigated to determine if blastogenesis induced by this mitogen was preceded by phosphoinositide turnover as previously shown for the lectins. Although periodate oxidation stimulated nucleic acid synthesis and interleukin-2 production, no changes in phosphoinositide turnover could be detected when compared to control lymphocyte cultures. These data indicate that increased phosphoinositide turnover is not an absolute prerequisite for lymphocyte proliferation.

Animals↗

PubMed1989

Thrombin's effects on osteoblastic cells. I. Cytosolic calcium and phosphoinositides.

Thrombin, a blood coagulation factor, has been shown to be a very effective in vitro bone resorbing agent whose mechanism of action on osteoblastic cells remains to be elucidated. In the present study, the effects of highly purified human thrombin on Saos-2 and G292 cells, two human osteoblast-like osteosarcoma cell lines, were investigated. Thrombin (0.6-16 U/ml) caused a significant, dose-dependent increase in osteoblastic cell proliferation. Thrombin also elicited a dose-dependent increase in cytosolic calcium concentration in both Saos-2 and G292 cells (maximal increases were 38% and 200% over baseline, respectively). Addition of thrombin to the osteoblast-like cells resulted in significant time- and dose-dependent changes in phosphoinositide levels: the percentage of inositol monophosphate levels were decreased, whereas the percentage of inositol bisphosphate, inositol trisphosphate and inositol tetrakisphosphate levels were increased. The relative magnitude of the changes in phosphoinositide levels was similar to the changes in cytosolic calcium concentration. These results suggest that thrombin's mechanism of action on bone cells may involve increases in cytosolic calcium levels and in phosphoinositide metabolism.

Bone Resorption↗

PubMed1992

Effect of high K+ exposure on phosphoinositide metabolism in frog skeletal muscle.

Using [3H]myo-inositol labeled frog skeletal muscles, we have studied the effect of high K+ exposure on phosphoinositide metabolism. After 12 hours labeling, 80mM K+ exposure induced a time-dependent change. The labeling associated with phosphatidylinositol (PI) and phosphatidylinositol 4-phosphate (PIP) gradually increased and decreased, respectively. The labeled phosphatidylinositol 4,5-bisphosphate (PIP2) first decreased, and then recovered. An accumulation of the labeling in inositol phosphates was shown. In shortening the labeling to 30 min, 15 min high K+ exposure was found to only increase the labeling in all fractions. Taken together, these results show that high K+ exposure can activate the turnover of phosphoinositides, which is consistent with the hypothesis that the metabolism of phosphoinositides may regulate excitation- contraction (e-c) coupling.

Animals↗