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PubMed1988

T cell receptor-mediated signaling occurs in the absence of inositol phosphate production.

Murine cytotoxic T lymphocytes (CTL) can lyse certain target cells in the presence or absence of extracellular Ca2+ (Ostergaard, H. L., Kane, K. P., Mescher, M. F., and Clark, W. R. (1987) Nature 330, 71-72). We have examined the effect of extracellular Ca2+ on the inositol phosphate response to antigen by CTL. In Ca2+-containing medium relevant antigen-bearing target cells and the mitogen concanavalin A induce a rapid accumulation of inositol phosphates in CTL. In the presence of 4 mM EGTA the antigen- and mitogen-stimulated increases in inositol mono-, bis-, and tris-phosphates cannot be detected, even with 10 mM LiCl added. Abrogation of the inositol phosphate response occurs whether CTL are preincubated in EGTA or EGTA is added with the stimulus. The results indicate that the killing of certain target cells by murine CTL may be independent of the involvement of the phosphatidylinositol pathway. Furthermore, since Ca2+-independent cytolysis remains antigen-specific, the data strongly support the existence of additional T cell receptor-mediated second messenger pathway(s) in CTL.

Calcium↗
PubMed1988

Activation of inositol phosphate formation by circulating noradrenaline but not by sympathetic nerve stimulation with a similar increase of glucose release in perfused rat liver.

In the isolated rat liver perfused in situ, stimulation of the nerve bundles around the hepatic artery and portal vein caused an increase of glucose and lactate output and a reduction of perfusion flow. These changes could be inhibited completely by alpha-receptor blockers. The possible involvement of inositol phosphates in the intracellular signal transmission was studied. 1. In cell-suspension experiments, which were performed as a positive control, noradrenaline caused an increase in glucose output and, in the presence of 10 mM LiCl, a dose-dependent and time-dependent increase of inositol mono, bis and trisphosphate. 2. In the perfused rat liver 1 microM noradrenaline caused an increase of glucose and lactate output and in the presence of 10 mM LiCl a time-dependent increase of inositol mono, bis and trisphosphate that was comparable to that observed in cell suspensions. 3. In the perfused rat liver stimulation of the nerve bundles around the portal vein and hepatic artery caused a similar increase in glucose and lactate output to that produced by noradrenaline, but in the presence of 10 mM LiCl there was a smaller increase of inositol monophosphate and no increase of inositol bis and trisphosphate. These findings are in line with the proposal that circulating noradrenaline reaches every hepatocyte, causing a clear overall increase of inositol phosphate formation and thus calcium release from the endoplasmic reticulum, while the hepatic nerves reach only a few cells causing there a small local change of inositol phosphate metabolism and thence a propagation of the signal via gap junctions.

Animals↗
PubMed1992

Neurotransmitters and neuropeptides stimulate inositol phosphates and intracellular calcium in cultured human nonpigmented ciliary epithelium.

The effects of several neurotransmitters and neuropeptides on the inositol phosphate/diacylglycerol pathway were examined in human nonpigmented ciliary epithelial cells. Maximal stimulation of inositol phosphate formation by vasopressin (approximately 3-fold), carbachol (approximately 2-fold) and histamine (approximately 5-fold) was observed only after cells had been confluent for at least six days. In contrast, a response to bombesin (approximately 3-fold) declined with extended time in confluent culture. Inositol monophosphate, inositol bisphosphate, and inositol trisphosphate all were stimulated by these agonists. Dose-response studies showed a close correlation between the EC50s of the different agonists when elevation of inositol phosphates was compared to stimulation of intracellular Ca2+, with the exception of bombesin. Preliminary pharmacologic characterization of the receptors for vasopressin, carbachol, and bombesin provided rank order of potencies for selective agonists and antagonists. The data suggest that the muscarinic receptor on human NPE cells is the M3 subtype, whereas the vasopressin receptor, as defined by its linkage to the inositol phosphate/diacylglycerol pathway, is the V1 subtype.

Analgesics↗
PubMed1989

Mass measurement of inositol phosphates.

This review summarises the methods available for the mass measurement of inositol phosphates, i.e., use of radioactive inositol lipid precursors, optical techniques, gas chromatography, mass spectrometry, nuclear magnetic resonance, fast atom bombardment and assays specific for Ins(1,4,5)P3. Examples of the use of each method, its sensitivity, advantages and drawbacks are given.

Animals↗
PubMed1995

Interferon-gamma increases intracellular calcium and inositol phosphates in primary human thyroid cell culture.

Interferon-gamma (IFN gamma) is believed to play a role in the pathogenesis of autoimmune thyroid disease, as it is known to exert diverse effects on thyroid metabolism. These include induction of human leukocyte antigen class II expression, inhibition of gene expression of thyroglobulin and thyroid peroxidase, as well as inhibition of cellular proliferation. However, the mechanism of action of IFN gamma in thyrocytes has not been clearly defined. We studied the action of IFN gamma on the production of inositol phosphates and intracellular Ca2+ mobilization in primary cultures of human thyrocytes using the fluorescent Ca2+ indicator fura-2. IFN gamma increased the production of inositol mono-, bis-, and trisphosphates and caused a dose-dependent increase in intracellular Ca2+ ([Ca2+]i) at 37 C. Preincubation with 12-O-tetradecanoylphorbol-13-acetate, which activates protein kinase C, resulted in the abolition of the IFN gamma response, suggesting that protein kinase C was involved in a negative feedback loop resulting in inhibition of IFN gamma-induced [Ca2+]i rise. Prior release of intracellularly stored Ca2+ with thapsigargin, the microsomal Ca2+ pump inhibitor, also abolished the response of IFN gamma. Mobilization of [Ca2+]i resulted in Ca2+ entry across the plasma membrane, which could be blocked by La3+, the inorganic Ca2+ antagonist. The tyrosine protein kinase inhibitor, genistein, inhibited the production of inositol phosphates and the elevation of [Ca2+]i induced by IFN gamma, but had no effect on ATP, suggesting that tyrosine protein kinase is involved in the signaling transduction of IFN gamma. We conclude that the mobilization of intracellular Ca2+ and the production of inositol phosphates are two important signaling events for the action of IFN gamma in human thyrocytes.

Alkaloids↗
PubMed1992

Preparation of samples for high-performance liquid chromatography of inositol phosphates.

A simple method is described for the removal of extraneous material from tissue extracts prior to anion-exchange high-performance liquid chromatography of inositol phosphates. Samples are prepared by extraction with trichloroacetic acid or perchloric acid followed by removal of the excess acid. The extracts are then passed through small Dowex-50 cation-exchange columns and eluted with water. Dowex-50 pretreatment removes most of the ultraviolet absorbing material and cations from the samples but does not alter the content of inositol phosphates. This treatment results in improved reliability of chromatography, especially with respect to weakly retained molecules such as adenosine 5'-phosphate and the isomers of inositol monophosphate. In addition, sample pretreatment improves the useful lifetime of the analytical anion-exchange columns.

Animals↗
PubMed1993

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on protein kinase C and inositol phosphate metabolism in primary cultures of rat hepatocytes.

Adult rat hepatocytes, after maintenance for 24 h in serum-free culture, were treated with the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate (TPA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Short-term treatment (15 min) with TPA, 1 microM, increased protein kinase C (PKC) activity in the particulate fraction of hepatocytes and, concomitantly, decreased the vasopressin (100 nM)-stimulated synthesis of inositol phosphates. The latter effect of TPA could be prevented by prior addition of the PKC inhibitor, H7 (100 microM). After short-term treatment (15 min) with TCDD, 1 pM, no effects on PKC or inositol phosphate metabolism were observed. However, after prolonged exposure to TCDD (3-48 h), the particulate PKC was significantly activated (1.5-fold). In contrast to the effect of TPA (24 h), no down-regulation was found. Moreover, long-term treatment with TCDD significantly enhanced vasopressin-stimulated inositol 1,3,4,5-tetrakisphosphate synthesis, while TPA treatment (24 h) stimulated the synthesis of inositol trisphosphates and inositol 1,3,4,5-tetrakisphosphate. The results suggest that the tumor promoters, TPA and TCDD, act differently on the signal transduction pathways in hepatocytes. Thus, the effects of TCDD on PKC and inositol phosphate metabolism might be mediated by a yet unknown mechanism rather than by direct activation of PKC as seen with TPA.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMedDate not supplied

Glutamate stimulates inositol phosphate formation in striatal neurones.

The major excitatory amino acids, glutamate (Glu) and aspartate (Asp), are thought to act at three receptor subtypes in the mammalian central nervous system (CNS). These are termed quisqualate (QA), N-methyl-D-aspartate (NMDA) and kainate (KA) receptors according to the specific agonist properties of these compounds revealed by electrophysiological studies. Although Glu has been shown to stimulate cyclic GMP formation in brain slices, direct regulation of second messenger systems (cyclic AMP, Ca2+ or inositol phosphates) subsequent to activation of excitatory amino-acid receptors, has not been extensively studied. Here we demonstrate that in striatal neurones, excitatory amino acids, but not inhibitory or non-neuroactive amino acids, induce a three- to fourfold increase in inositol mono-, di- and triphosphate (IP, IP, IP) formation with the relative potency QA greater than Glu greater than NMDA, KA. The Glu-evoked formation of inositol phosphates appears to result principally from actions at QA as well as NMDA receptors on striatal neurones. Our results suggest that excitatory amino acids stimulate inositol phosphate formation directly, rather than indirectly by the evoked release and subsequent actions of adenosine or acetylcholine.

2-Amino-5-phosphonovalerate↗
PubMed1990

A comparison of the effects of divalent and trivalent cations on parathyroid hormone release, 3',5'-cyclic-adenosine monophosphate accumulation, and the levels of inositol phosphates in bovine parathyroid cells.

We compared the effects of a series of di- and trivalent cations on various aspects of parathyroid function to investigate whether these polyvalent cations act on the parathyroid cell through a similar mechanism. Like high extracellular concentrations of Ca2+, high levels of barium (Ba2+), strontium (Sr2+), gadolinium (Gd3+), europium (Eu3+), terbium (Tb3+), and ytterbium (Yb3+) [corrected] each inhibited low calcium-stimulated PTH release and showed IC50 values (the concentration producing half of the maximal inhibitory effect) of 1.12 mM, 1.18 mM, 2.2 microM, 2.5 microM, 0.89 microM, and 15 microM, respectively. The inhibitory effects of both divalent (Ca2+ and Ba2+) and trivalent (Gd3+) cations were reversible by 76-100% after removal of the cation, suggesting that the polyvalent cation-mediated reduction in PTH release was not due to nonspecific toxicity. The same di- and trivalent cations produced an 80-90% decrease in agonist-stimulated cAMP accumulation with a similar order of potency as for their effects on PTH release. Preincubation overnight with pertussis toxin totally prevented the inhibitory effects of the trivalent cations on cAMP accumulation. The same di- and trivalent cations also increased the accumulation of inositol monophosphate, inositol bisphosphate, and inositol trisphosphate. Their effects on this parameter differed from those on PTH release and cAMP accumulation in several respects. First, Ba2+ and Sr2+, rather than being equipotent with Ca2+, were about 2-fold less potent in increasing the levels of inositol phosphates. Second, the trivalent cations were 5-50-fold less potent in raising inositol phosphates than in modulating PTH release and cAMP accumulation, and all were nearly equipotent. These results show that trivalent cations of the lanthanide series mimic the actions of divalent cations on several aspects of parathyroid function, and likely do so by interacting with the cell surface "Ca2(+)-receptor-like mechanism" through which extracellular Ca2+ has been postulated to act. The pharmacology of the effects of these polyvalent cations on cAMP and PTH release are similar and differ from that for their actions on inositol phosphate metabolism, raising the possibility that there might be more than one form of the putative Ca2+ receptor.

Animals↗
PubMed2000

Suppression of inositol phosphate release by cardiac myocytes isolated from fish oil-fed pigs.

Fatty acid composition of cardiac myocytes and release of inositol phosphates in pigs fed a fish oil supplemented diet was examined. Two groups of female pigs were fed diets supplemented with either 50 g/kg diet beef tallow (as control) or 50 g/kg diet fish oil (MaxEPA) rich in n-3 fatty acids. After 6 weeks of supplementation, the pigs were anesthetized and hearts were removed. Cardiac myocytes were isolated, lipid extracted and separated into non-polar and polar lipids by thin-layer chromatography. Fatty acid composition of individual neutral and polar lipid classes were examined by gas chromatography. To study the effect of membrane phospholipid modification on the phospholipase C (PLC) mediated release of inositol phosphates, cardiac myocytes were labelled with 4 microCi/mL myo-[2-(3)H]inositol for 48 h. After stimulation with epinephrine and phenylephrine, the water soluble [3H]inositol products were extracted, separated from [3H]inositol and [3H]glycerophosphoinositol by chromatography on Dowex AG 1-X8 and quantitated by scintillation counting. Cardiac myocytes isolated from fish oil-fed pigs had higher levels of n-3 polyunsaturated fatty acid in the non-esterified fatty acid and phospholipid fraction. Similarly, these cardiac myocytes had increased level of n-3 fatty and decreased n-6 fatty acids in all the phospholipid fractions, PE, PC, P1 and PS (p < 0.05). After stimulation, the levels of [3H]inositol trisphosphate (IP3) and [3H]inositol tetrakisphosphate (IP4) in cardiac myocytes isolated from fish oil-fed pigs were significantly reduced (p < 0.05) compared to myocytes isolated from beef tallow fed-pigs. This study for the first time has utilised adult cardiac myocytes to demonstrate the effect of n-3 PUFA supplementation on cardiac myocyte phospholipid fatty acid composition and release of second messengers.

Animals↗
PubMed2002

Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance.

Inositol phospholipids and inositol phosphates mediate well-established functions in signal transduction and in Ca2+ homeostasis in the CNS and non-neural tissues. More recently, there has been renewed interest in other roles that both myo-inositol and its highly phosphorylated forms may play in neural function. We review evidence that myo-inositol serves as a clinically relevant osmolyte in the CNS, and that its hexakisphosphate and pyrophosphorylated derivatives may play roles in such diverse cellular functions as DNA repair, nuclear RNA export and synaptic membrane trafficking.

Animals↗
PubMed1992

Aldosterone enhances angiotensin II receptor binding and inositol phosphate responses.

Clinical states in which angiotensin II is increased are often associated with increases in mineralocorticoids. To determine the effects of mineralocorticoids on angiotensin II action, we examined the effects of aldosterone on angiotensin II receptor expression and function in cultured rat vascular smooth muscle cells. Incubation with aldosterone resulted in concentration- and time-dependent increases in angiotensin II receptor number, without changes in binding affinity. For example, incubation with 1 microM aldosterone for 40 hours resulted in 59% increases in angiotensin II receptor number. Increases in angiotensin II receptors were dependent on protein synthesis as evidenced by the time dependency of upregulation and inhibition by cycloheximide. Incubation with aldosterone resulted in enhanced angiotensin II-stimulated phospholipase C activation, as demonstrated by increases in angiotensin II-induced inositol phosphate responses in proportion to the increases in receptor number. In addition, aldosterone prevented angiotensin II-induced downregulation of angiotensin II surface receptors and angiotensin II desensitization of inositol phosphate formation. In summary, aldosterone 1) directly increased angiotensin II receptor number, 2) increased angiotensin II-stimulated inositol phosphate responses, and 3) prevented angiotensin II-induced downregulation and desensitization. In conclusion, aldosterone may potentiate the pressor responses of angiotensin II via effects on angiotensin II receptors.

Aldosterone↗
PubMed1990

Endometrial inositol phosphate turnover in pigs is reduced during pregnancy and estradiol-induced pseudopregnancy.

Three experiments were conducted to examine inositol phosphate (IP) turnover in response to treatments applied in vitro to endometrium from cyclic (CYC), pregnant (PREG) and estradiol-induced pseudopregnant (PSP) gilts. In Exp. 1, treatments (in 25 microliters .1 M NaHCO3) were 1) control (NaHCO3), 2) 125 ng oxytocin, 3) .25 micrograms prolactin, 4) 2.5 micrograms prolactin and 5) 5 micrograms pig conceptus secretory proteins (pCSP). Basal IP turnover on d 14 (estrus = d 0) for CYC was 3.9 to 5.0-fold greater than for PREG gilts and .6 to 1.1-fold greater than for PSP gilts (P less than .05). Oxytocin increased IP turnover 23 to 42% in CYC gilts (P less than .05), but not in PREG or PSP gilts. The treatment x reproductive status interaction (P less than .05) indicated that pCSP increased IP turnover 74 to 140% in PREG gilts but decreased it 18 to 22% in CYC and 17 to 50% in PSP gilts. In Exp. 2, treatments were applied in a 2 x 2 x 2 arrangement: 1) 0 or 125 ng oxytocin; 2) 0 or 2.5 micrograms prolactin and 3) 0 or 5 micrograms pCSP. Basal IP turnover on d 14 was 3.3 to 5.4-fold greater (P less than .05) in CYC than in PSP gilts and was affected by interaction (P less than .05) of pCSP and prolactin. Inositol phosphate turnover was increased by prolactin (12 to 22%) and by pCSP (7 to 34%) but, when combined, the stimulatory effects of each were eliminated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Inositol phosphate structural requisites for Ca2+ influx.

To understand how inositol phosphates (InsP) cause Ca2+ influx, we injected 37 highly purified compounds containing a total of 49 InsP positional isomers into Xenopus oocytes. The eight InsP that stimulated Ca2+ influx were those that had the highest potency at releasing intracellular Ca2+, indicating that their common target was the inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor. To cause Ca2+ influx, these InsP had to be injected in a much higher concentration than the minimal concentration required to release intracellular Ca2+. Such high InsP concentrations could inhibit ongoing oscillatory intracellular Ca2+ release. In addition, we found that InsPs could not elicit further intracellular Ca2+ release during the course of Ca2+ influx. Our data are consistent with the "capacitative Ca2+ entry" hypothesis, which states that InsP stimulate Ca2+ influx by depleting the InsP-sensitive intracellular Ca2+ store. In this context, we would suggest that to deplete the InsP-sensitive intracellular Ca2+ store, InsP may have to be present in a sufficiently high concentration to override the oscillatory Ca(2+)-refilling mechanisms of the stores.

Animals↗
PubMed1988

Inositol phosphate production and Ca2+ mobilization in human umbilical-vein endothelial cells stimulated by thrombin and histamine.

Human umbilical-vein endothelial cells (HUVECs) were cultured, and their inositol phosphate formation and Ca2+ mobilization in response to thrombin and histamine were studied. Evidence from measurement of intracellular Ca2+ in the absence of extracellular Ca2+ established that the two agonists were both acting on a single cell population, and suggested that a Ca2+-influx component was stimulated which was dependent on receptor-occupancy. After 30 s of stimulation in the presence of 10 mM-LiCl, the effects of 20 microM-histamine and 1 unit of thrombin/ml on formation of inositol phosphates were additive, but at 5 min they were not. HUVECs labelled with myo-[3H]inositol for 72 h synthesized radiolabelled inositol pentakis- and hexakis-phosphate. The predominant isomers of inositol mono-, bis- and tris-phosphates whose formation was stimulated were the 4-phosphate, the 1,4-bisphosphate and the 1,3,4-trisphosphate.

Calcium↗
PubMed1994

Inositol phosphates inhibit uptake and transport of iron and zinc by a human intestinal cell line.

To examine the influence of inositol phosphates on the uptake and absorption of Fe and Zn, Caco-2 cells were grown on either plastic (uptake studies) or porous membranes in bicameral chambers (transport/absorption studies). Caco-2, a human colon adenocarcinoma cell line, was selected as the test cell because it spontaneously differentiates into polarized enterocyte-like cells at confluency. Uptake of Fe (added as Fe-nitrilotriacetate complex) from a calcium-free solution by fully differentiated cells was 37 pmol/cm2. Addition of 10-fold molar excess of individual inositol phosphates (IP3, IP4, IP5 or IP6) decreased Fe solubility by 13 to 25% and reduced Fe uptake by 50 to 65%. The rate of transport of Fe from the apical solution into the basolateral chamber [1.4 +/- 0.1 pmol/(h.cm2)] decreased (34-96%) in proportion to the degree of phosphorylation of the inositol derivative in the apical compartment. Uptake and transepithelial transport of Zn were 246 +/- 5 pmol/cm2 and 23 +/- 1 pmol/(h.cm2), respectively. The solubility, uptake and rate of transport of Zn also decreased in proportion to the degree of phosphorylation of inositol. These results demonstrate the inhibitory influence of IP3-IP6 on the uptake and transport of Fe and Zn and support the usefulness of the Caco-2 human cell line as an appropriate model for evaluating the effects of specific dietary factors on trace metal bioavailability.

Colonic Neoplasms↗
PubMed2005

The differential effects of the gonadotropin receptors on aromatase expression in primary cultures of immature rat granulosa cells are highly dependent on the density of receptors expressed and the activation of the inositol phosphate cascade.

Signaling pathways mediating the divergent effects of FSH and LH on aromatase in immature rat granulosa cells were studied by infecting cells with increasing amounts of adenoviral vectors for the human LH receptor (hLHR) or FSH receptor (hFSHR). Increasing amounts of Ad-hLHR, used at a multiplicity of infection (MOI) of 20 or 200 viable viral particles/cell, increased human chorionic gonadotropin (hCG) binding and hCG-induced cAMP and Akt phosphorylation, but inositol phosphates only increased in response to hCG in cells infected with 200 MOI Ad-hLHR. In contrast, hCG increased aromatase expression in cells infected with 20, but not in cells infected with 200, MOI Ad-hLHR. Cells infected with 20 or 200 MOI Ad-hFSHR showed increased hFSH binding and hFSH-induced Akt phosphorylation, but the hFSH-induced cAMP response was unchanged relative to control cells. However, hFSH was able to stimulate the inositol phosphate cascade in the Ad-hFSHR-infected cells, and the hFSH induction of aromatase was abolished. We also found that activation of C kinase or expression of a constitutively active form of Galphaq inhibited the induction of aromatase by hFSH or 8Br-cAMP. We conclude that the differential effects of FSH and LH on aromatase in immature granulosa cells are highly dependent on gonadotropin receptor density and on the signaling pathways activated. We propose that aromatase is induced by common signals generated by activation of the FSHR and LHR (possibly cAMP and Akt) and that the activation of the inositol phosphate cascade in cells expressing a high density of LHR or FSHR antagonizes this induction.

Adenoviridae↗
PubMed1996

Carbachol stimulates inositol phosphate formation transiently in Trypanosoma cruzi.

The effect of carbachol on Trypanosoma cruzi epimastigote forms was studied. Suspension of epimastigote cells prelabelled with myo[3H]-inositol were incubated at 28 degrees C in the presence of carbachol. The levels of inositol phosphate after the challenge of carbachol were determined to see if the accumulation of inositol phosphate was time-dependent. In the presence of Li+ the levels of IP3 and IP4 were significantly increased during the 3 min. with a peak at 1 min. after the carbachol challenge. This effect was suppressed by atropine. The results show that carbachol influences rapid changes in phosphoinositide metabolism and they are time-dependent involving second-messenger systems associated with the generation of IP3. In addition they would suggest that this IP3 generation is through a receptor-mediated process linked to phospholipase C by a G-protein.

Animals↗