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PubMed1992

Di-myo-inositol-1,1'-phosphate: a new inositol phosphate isolated from Pyrococcus woesei.

A new inositol derivative could be isolated from the Archaeum Pyrococcus woesei and identified as di-myo-inositol-1,1'-phosphate by 1H, 31P NMR spectroscopy, mass spectrometry and thin layer chromatography. In P. woesei, this inositol phosphate represents the dominant counterion of K+ which ranges from 500 to 600 mM. The role of the potassium salt of di-myo-inositol-1,1'-phosphate as thermostabilizer is discussed.

Archaea↗
PubMed1984

Inositol 1,4,5-trisphosphate stimulates phosphorylation of a 62,000-dalton protein in monkey fibroblast and bovine brain cell lysates.

Inositol 1,4,5-trisphosphate (IP3) is produced in cells as a breakdown product of the diphosphorylated form of phosphatidylinositol, phosphatidylinositol 4,5-bisphosphate. Stimulated breakdown of phosphoinositides has been correlated with a wide variety of hormonal stimuli which mobilize intracellular calcium, and IP3 has recently been found to cause calcium release from intracellular stores, thus implicating it as a second messenger in hormonal stimulation. In this paper we have examined the effect of IP3 on protein phosphorylation, and have found that IP3 stimulates phosphorylation of a 62-kDa protein in cell lysates made from cultured monkey fibroblasts and from bovine brain. Fifty per cent maximal stimulation of phosphorylation of this protein occurred at 2.5 X 10(-7) M IP3. Other inositol phosphates (inositol 1,4-bisphosphate, inositol 1-phosphate, inositol hexaphosphate, and myo-inositol) had no effect on protein phosphorylation at 10(-6)M, although inositol 1,4-bisphosphate at higher concentrations enhanced phosphorylation of the 62-kDa protein in brain lysates. The IP3-stimulated phosphorylation was calcium-independent and did not appear to result from inhibition of an endogenous protein phosphatase. We suggest that IP3, like other second messengers, acts as a protein kinase regulator.

Animals↗
PubMed1989

Differential activation of human skin cells by platelet activating factor: stimulation of phosphoinositide turnover and arachidonic acid mobilization in keratinocytes but not in fibroblasts.

Treatment of cultured adult human keratinocytes with platelet activating factor (PAF) resulted in a rapid, dose dependent accumulation of inositol phosphates. Inositol trisphosphate (IP3), inositol bisphosphate (IP2) and inositol phosphate (IP) were elevated within 15 seconds of exposure to PAF (1 microM). Lyso-PAF, phosphatidylcholine (PC) and lyso-PC had no effect on levels of inositol phosphates, indicating that the effect of PAF was specific. PAF also raised cellular 1,2-diacylglycerol content (2-fold) within two minutes of addition and stimulated mobilization of arachidonic acid (AA) and release of prostaglandin E2. In contrast, PAF did not stimulate phosphoinositide turnover or AA release in cultured dermal fibroblasts. These results suggest that the inflammatory effects of PAF in human skin result, at least in part, from its ability to directly activate keratinocytes and stimulate release of pro-inflammatory eicosanoids.

Adult↗
PubMed1990

Autocrine motility factor stimulates a three-fold increase in inositol trisphosphate in human melanoma cells.

The biochemical pathways through which tumor cell locomotion is mediated are poorly understood. Autocrine motility factor (AMF), which is produced by and stimulates motility in A2058 human melanoma cells, was used to characterize phosphoinositide (PtdIns) metabolism activated in association with tumor cell motility. AMF stimulated up to a 400% increase in de novo incorporation of 3H-myo-inositol into cellular lipids beginning 40 minutes after exposure. In cells prelabeled with 3H-myo-inositol, AMF stimulated a 200% increase in total inositol phosphates (inositol monophosphate, InsP1; inositol bisphosphate, InsP2; inositol trisphosphate, InsP3) after 90 minutes of exposure, with a 300% maximal increase in InsP3 at 120 minutes. InsP1 and InsP2 were maximally increased 130% of control values. Treatment with AMF stimulated a parallel dose-dependent increase in both motility and PtdIns levels. We have shown previously that the A2058 motile response to AMF is inhibited markedly by cell pretreatment with pertussis toxin (PT). Inositol phosphate production was inhibited by a 2-hour pretreatment of cells with PT (0.5 microgram/ml). PT treatment of A2058 membranes was associated with ADP-ribosylation of a 40-kDa protein consistent with the presence of an alpha subunit of a guanine nucleotide-binding protein (G protein). These data indicate that AMF elicits increases in cell motility and phosphoinositide metabolism via a PT-sensitive G protein signal transduction pathway.

Adenosine Diphosphate Ribose↗
PubMed1986

Diminished agonist-stimulated inositol trisphosphate generation blocks stimulus-secretion coupling in mouse pancreatic acini during diet-induced experimental pancreatitis.

Young female mice fed a choline-deficient, ethionine-supplemented (CDE) diet rapidly develop acute hemorrhagic pancreatitis. We have observed that pancreatic acini prepared from these mice are unable to secrete amylase in response to addition of the cholinergic agonist carbachol, although they retain the ability to secrete amylase in response to the Ca2+ ionophore A23187. The CDE diet does not alter the binding characteristics (Kd or the maximal number of binding sites) for muscarinic cholinergic receptors as tested using the antagonist [3H]N-methylscopolamine nor the competition for this binding by carbachol. Addition of carbachol to acini prepared from mice fed the CDE diet does not result in as marked an increase in cytosolic free Ca2+ levels as that noted in control samples (evaluated using quin2 fluorescence). These observations indicate that the CDE diet interferes with stimulus-secretion coupling in mouse pancreatic acini at a step subsequent to hormone-receptor binding and prior to Ca2+ release. This conclusion is confirmed by our finding that the hormone-stimulated generation of [3H]inositol phosphates (inositol trisphosphate, inositol bisphosphate, and inositol monophosphate) from acini labeled with [3H]myoinositol is markedly reduced in acini prepared from mice fed the CDE diet. This reduction is not due to a decrease in phosphatidylinositol-4,5-bisphosphate. This communication represents the first report of a system in which a blockade of inositol phosphate generation can be related to a physiologic defect and pathologic lesion.

Aminoquinolines↗
PubMed1991

Receptors and neurosecretory actions of endothelin in hypothalamic neurons.

Primary cultures of rat hypothalamic neurons were found to secrete the potent calcium-mobilizing and mitogenic peptide endothelin (ET) and to contain specific ET binding sites with higher affinity for ET-1 and ET-2 than ET-3. ET receptors of similar specificity were also identified in two gonadotropin-releasing hormone (GnRH) neuronal cell lines (GT1-1 and GT1-7). In both primary cultures and GnRH neurons, receptor binding of ETs led to marked and dose-dependent increases of inositol phosphates; inositol bis-, tris-, and tetrakisphosphates increased promptly, reached a peak within 2 min, and returned toward the steady-state levels during the next 10 min. ET-1 was more potent than ET-3 in mobilizing inositol phosphates, consistent with its greater affinity for the ET receptors in these cells. ET also stimulated GnRH secretion from perifused hypothalamic cultures and GnRH cell lines, with a sharp increase followed by a prompt decline to the basal level. These data show that ET is produced in the hypothalamus and acts through calcium-mobilizing ET receptors in normal and transformed secretory neurons to stimulate GnRH release. These actions of locally produced ETs upon GnRH-secreting neurons indicate that the vasoconstrictor peptides have the capacity to regulate neurosecretion and could participate in the hypothalamic control of anterior pituitary function and gonadotropin secretion.

Animals↗
PubMed1982

Enantiomeric Form of myo-Inositol-1-Phosphate Produced by myo-Inositol-1-Phosphate Synthase and myo-Inositol Kinase in Higher Plants.

The product of myo-inositol-1-phosphate synthase, EC 5.5.1.4, from mature pollen of Lilium longiflorum Thunb., cv Ace (Easter lily) and that of myo-inositol kinase, EC 2.7.1.64, from wheat germ has been identified as 1l-myo-inositol-1-phosphate by gas chromatography of its trimethylsilyl-methyl phosphate derivative on a glass capillary column bearing a chiral phase.

Journal Article↗
PubMed1996

The positive inotropic effect and the hydrolysis of phosphoinositide induced by endothelin-3 in rabbit ventricular myocardium: inhibition by a selective antagonist of ET(A) receptors, FR139317.

Endothelin-3 (ET-3), an isopeptide of ET, had a concentration-dependent positive inotropic effect (PIE) on rabbit papillary muscle. The maximal inotropic response to ET-3 was 65% of the maximal response to isoproterenol. ET-1 elicited a PIE below 10(-9) M, namely, over a concentration range at which ET-3 did not elicit a PIE. The selective ET(A) antagonist FR139317 effectively antagonized the PIE of ET-3. FR139317 abolished the PIE induced by ET-1 (<10(-9)M) but did not inhibit the PIE induced by high concentrations of ET-1. FR139317 also antagonized the PIE of sarafotoxin S6c. ET-3 caused a time- and concentration-dependent increase in [3H]inositol phosphates (inositol monophosphate, inositol bisphosphate and inositol trisphosphate). FR139317 at 10(-5) M decreased the ET-3-induced increase in inositol phosphates by about 60%, whereas it attenuated the increase in [3H]IP1 induced by ET-1 (3 x 10(-8)M) by only 20%. Thus, in the presence of FR139317, the PIEs of ET-3 and ET-1 were partially dissociated from the PI hydrolysis that was induced by these isopeptides. FR139317 inhibited the specific binding of [125I]ET-1 and of [125I]ET-3, and it was apparent that FR139317 had a high-affinity and a low-affinity site for competing for specific binding with each ligand. These findings indicate that different subtypes of the ET receptor are involved in the induction of the PIEs of ET-3 and ET-1. The PIE of ET-3 may be mediated predominantly by ET(A1) receptors that are susceptible to FR139317 and BQ-123 and partially by ET(B) receptor that are inhibited by RES-701-1. Both ET(A1) and ET(A2) receptors may be responsible for the PIE of ET-1, depending on the concentration in rabbit ventricular myocardium.

Animals↗
PubMed1968

The mechanism of glucose 6-phosphate-D-myo-inositol 1-phosphate cyclase of rat testis. The involvement of hydrogen atoms.

Comparison of the initial (3)H/(14)C ratios in specifically labelled d-glucose 6-phosphates with the final ratios in myo-inositol produced by glucose 6-phosphate-d-myo-inositol 1-phosphate cyclase from rat testis showed that, during the conversion, the hydrogen atoms at C-1 and C-3 were fully retained, one hydrogen atom was lost from C-6, and that at C-5 was apparently retained to the extent of 80-90%. The loss of (3)H could not be stimulated by addition of unlabelled NADH, and when unlabelled substrate was used (3)H from [(3)H]NADH and [(3)H]water was not incorporated. Treatment of the enzyme with charcoal abolished the activity, and this was restored to 25-50% of the original activity by NAD(+). The charcoal-treated enzyme again apparently gave 85% retention of hydrogen with [5-(3)H]glucose 6-phosphate as substrate in the presence of NAD(+) alone, but the retention was decreased to 65% with excess of NADH. The results are interpreted as indicating that the cyclization proceeds by an aldol condensation in which C-5 is oxidized by NAD(+) in a tightly-bound ternary complex, and that the apparent loss of (3)H when untreated enzyme is used is due to an isotope effect. It is suggested that after treatment with charcoal some exchange of NADH with an external pool may take place.

Animals↗
PubMed1989

Rapid dephosphorylation of protein kinase C substrates by protein kinase A activators results from inhibition of diacylglycerol release.

The biochemical events encompassing the dephosphorylation of protein kinase C substrates by protein kinase A activators have been investigated in a neurotumor cell line, NCB-20. Treatment of [32P]orthophosphate-labeled cells with protein kinase A activators (e.g. forskolin, dibutyryl cAMP, prostaglandin E1) resulted in an inhibition of protein kinase C activity due to a failure of the protein kinase C complex to translocate into the membrane. Phospholipase C activity, as measured by the synchronous release of diacylglycerol and inositol phosphates (inositol 1,4,5-trisphosphate, inositol 1,4-bisphosphate, and inositol 1-phosphate) in response to bradykinin, was inhibited up to 50% following exposure to protein kinase A activators. At the same time, phospholipase C-specific inositol phospholipid substrates (phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate) were found to accumulate in NCB-20 cells following treatment with protein kinase A activators. This suggests that phospholipase C may be altered through protein kinase A-mediated protein phosphorylation. Second messenger generation (inositol phosphates, diacylglycerol, and Ca2+) is therefore inhibited through cyclic AMP-mediated shutdown of the inositol lipid cycle at the level of phospholipase C.

1-Methyl-3-isobutylxanthine↗
PubMed2000

The 6-OH group of D-inositol 1-phosphate serves as an H-bond donor in the catalytic hydrolysis of the phosphate ester by inositol monophosphatase.

Inositol monophosphatase plays a pivotal role in the biosynthesis of secondary messengers and is believed to be a target for lithium therapy. It is established how a lithium ion works in inhibiting the enzyme but details of the mechanism for the direct magnesium ion activated hydrolysis of the substrate have been elusive. It is known that substrates require a minimal 1,2-diol phosphate structural motif, which in D-myo-inositol 1-phosphate relates to the fragment comprising the 1-phosphate ester and the 6-hydroxy group. Here it is shown that inhibitors that are D-myo-inositol 1-phosphate substrate analogues possessing 6-substituents larger than the 6-hydroxy group of the substrate, for example, the 6-O-methyl analogue, are able to bind to the enzyme in a congruous manner to the substrate. It is demonstrated, however, that such compounds show no substrate activity whatsoever. It is also shown that a 6-amino group is able to fulfil the role of the 6-hydroxy group of the substrate in conferring substrate activity and that a 6-methylamino group is similarly able to support catalysis. The results indicate that a 6-substituent capable of serving as a hydrogen-bond donor is required in the catalytic mechanism for hydrolysis. It has recently been shown that inositol is displaced from phosphorus with inversion of stereochemistry and we expect that the nucleophilic species is associated with Mg(2+)-1. It is proposed here that the role of the 6-hydroxy group of the substrate is to H-bond with a water molecule or hydroxide ion located on Mg(2+)-2. From this analysis, it appears that the water molecule bound to Mg(2+)-2 serves as a proton donor for the inositolate leaving group in a process that stabilises the alkoxide product and retards the back-reaction.

Animals↗
PubMed2002

Enantiodivergence in small-molecule catalysis of asymmetric phosphorylation: concise total syntheses of the enantiomeric D-myo-inositol-1-phosphate and D-myo-inositol-3-phosphate.

Peptide-based catalysts have been found that catalyze the enantiodivergent phosphorylation of a meso myo-inositol-derived triol (1). The sequential screening of random peptide libraries, followed by the evaluation of a focused library, led to the identification of two peptides (2 and 24) that are complementary in producing enantiomeric D-myo-inositol-1-phosphate and D-myo-inositol-3-phosphate derivatives. The catalysts were then used to complete efficient total syntheses of both D-I-1P and D-I-3P in optically pure form. Additional information is gleaned from relative rate experiments that unambiguously show the catalysts to afford enantioselection through rate accelerative pathways with respect to simple achiral alkylimidazole catalysts. Furthermore, solvent effect studies show that the two enantiodivergent catalysts exhibit different tolerances of polar media. The systematic discovery of site-selective catalysts establishes a basis for future studies of chiral catalysts that differentiate unique functional groups in polyfunctional molecules.

Catalysis↗
PubMed1977

Hydrogen isotope effects in the cyclization of D-glucose 6-phosphate by myo-inositol-1-phosphate synthase.

myo-Inositol-1-phosphate synthase (EC 5.5.1.4) from rat testis, Acer pseudoplatanus L. cell culture and Oryza sativa L. cell culture, converted D-[5-3H]glucose 6-phosphate to myo-[2-3H]inositol 1-phosphate at rates ranging from 0.21 to 0.48 that of unlabeled substrate. D-[3-3H]- and D-[4-3H]glucose 6-phosphate were converted at approximately the same rate as that of unlabeled substrate. In the case of testis enzyme, storage as a frozen solution further lowered the rate with D-[5-3H]glucose 6-phosphate as substrate. When the reaction was run in [3H]water, no 3H appeared in myo-inositol 1-phosphate but a small amount was recovered in substrate isolated from the final reaction mixture. These data support the involvement of carbon 5 of D-glucose 6-phosphate in the mechanism proposed for this conversion.

Animals↗
PubMed1988

Enhanced phosphodiesteratic breakdown and turnover of phosphoinositides during reperfusion of ischemic rat heart.

In this study, we examined phosphoinositide metabolism during ischemia and reperfusion using an isolated and perfused rat heart. When myocardial phosphoinositides were prelabeled with [3H]inositol, reperfusion after 30 minutes of normothermic global ischemia resulted in significant accumulations of radiolabeled inositol phosphate, inositol bisphosphate, and inositol trisphosphate. Isotopic incorporation of [3H]inositol into phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-bisphosphate was increased significantly in the heart reperfused with [3H]inositol after 30 minutes of ischemia compared with that perfused with [3H]inositol after 30 minutes of nonischemic perfusion. However, isotopic incorporation of [3H]glycerol into diacylglycerol, phosphatidic acid, and all of the three phosphoinositides was diminished in the reperfused hearts. Reperfusion of the ischemic heart prelabeled with [14C]arachidonic acid resulted in significant increases in [14C]diacylglycerol and [14C]phosphatidic acid. The enhanced accumulations of [3H]inositol phosphates during reperfusion were not affected by treatment with prazosin plus atropine or indomethacin, but were inhibited by hypoxic reperfusion, reperfusion with Ca2+-free buffer, or by mepacrine. These results suggest that myocardial reperfusion stimulates phosphodiesteratic breakdown and turnover of phosphoinositides, and increased Ca2+ influx caused by reperfusion may be involved in the mechanism of stimulation of phosphatidylinositol-specific phospholipase C activity in the rat heart.

Animals↗
PubMed2003

1H NMR titrations of hydroxy protons in aqueous solution as a method of investigation of intramolecular hydrogen-bonding in phosphorylated compounds: examples of myo-inositol 2-phosphate and myo-inositol 1,2,6-tris(phosphates).

1H NMR hydroxy proton titration experiments for myo-inositol 2-phosphate and myo-inositol 1,2,6-tris(phosphates) in aqueous solution are presented to demonstrate that by following OH signals versus pH, evidence can be brought for HB interaction between the hydroxyl and phosphate groups. The chemical shifts of the OH protons vicinal to phosphate groups appear deshielded by ca. 2.5 ppm with regard to those two centers removed from the phosphates. Remarkably, the deshielded protons are only present when their neighboring phosphate groups are fully deprotonated but persist until high pHs. From these results, C-OH...2-O3P-O type I, C-HO...-HO3P-O type II and C-OH...-HO3P-O type III hydrogen bonds are evidenced and discussed.

Hydrogen Bonding↗
PubMed1990

Interleukin-1 stimulates diglyceride accumulation in the absence of protein kinase C activation.

Despite advances in the knowledge of the intracellular signalling in response to extracellular messengers, the mechanism of action of interleukin-1 (IL-1) has remained an enigma. In the present study, we have employed human dermal fibroblasts (Detroit 532 cells) to investigate IL-1 beta-induced changes in intracellular signals. Both recombinant human IL-1 beta and a native preparation purified from human placental tissue were employed. Cyclic AMP levels in cell monolayers were unaltered by IL-1 beta. Also, IL-1 beta did not influence significantly the levels of phosphatidylinositol, phosphatidylinositol 4-monophosphate, and phosphatidylinositol 4,5-bisphosphate in the membrane, nor the water-soluble inositol phosphates, inositol monophosphate, inositol bisphosphate and inositol trisphosphate, in cells prelabelled with myo-[3H]inositol. In addition, intracellular calcium as measured by Quin2 was unaffected by interleukin-1. However, in cells labelled with [3H]glycerol or [3H]arachidonic acid, IL-1 beta caused an immediate rise in diglyceride (DG) accumulation. As the effects of IL-1 beta have been reported to be mimicked by tumour-promoting phorbol esters, this rise in DG suggested the involvement of protein kinase C (PKC). However, repeated experiments failed to reveal any acute effect of IL-1 beta on the activity of this enzyme. Furthermore, IL-1 beta did not cause the translocation of PKC between the membrane and the cytosol as has been found in response to other extracellular signals. Rather, IL-1 beta appeared to increase the synthesis of PKC in both membrane and cytosol preparations, an effect which could be prevented by coincubation with cycloheximide. These findings suggest that the diglyceride formed in response to IL-1 beta does not activate protein kinase C.

Calcium↗
PubMed1988

Dopamine has no effect on thyrotropin-releasing hormone mobilization of calcium from intracellular stores in rat anterior pituitary cells.

To investigate whether dopaminergic reduction of PRL secretion is caused by an inhibition of release of Ca2+ from intracellular stores, we used a perifusion system to monitor simultaneously changes in intracellular Ca2+ concentrations ([Ca2+]c) and changes in PRL secretion from rat anterior pituitary cells, and from enriched populations of lactotrophs. We eliminated influx of extracellular Ca2+ by using medium with no added Ca2+ and 0.2 mM EGTA, conditions which abolished the increase in [Ca2+]c caused by 56 mM KCl. In this low Ca2+-containing medium, 100 nM TRH induced a burst of [Ca2+]c; the magnitude of the peak was the same whether the cells were perifused with low Ca2+-containing medium for 2 or 20 min before adding TRH, indicating the source of intracellular Ca2+ was stable under these conditions. After 2 min in this medium, TRH was still able to stimulate almost as much PRL release as in medium containing 1.8 mM Ca2+, and 1 microM dopamine inhibited this release, but did not affect the magnitude of the TRH-induced increase in [Ca2+]c. Preincubation for 5 min with dopamine did not affect the ability of a 30-sec incubation with TRH to stimulate the accumulation of inositol phosphate, inositol bisphosphate, and inositol trisphosphate, either in medium containing 1.8 mM Ca2+, or in low Ca2+-containing medium. Preincubation with dopamine for 5 min had no effect on TRH-induced mobilization of intracellular calcium. A source of Ca2+ is needed to refill internal Ca2+-stores discharged by TRH, and as dopamine lowered [Ca2+]c which might fill these stores, we tested to see if dopamine prevented.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Action and formation of inositol bisphosphate and inositol trisphosphate in rat anterior pituitary cells.

Inositol 4,5-bisphosphate and inositol 1,4,5-trisphosphate, administered exogenously at a concentration of 3 x 10(-5) mol/l increased LH release in superfused rat pituitary cells by 950 +/- 267% and 281 +/- 83%, respectively. This stimulatory effect was reversible and dose-dependent. Other inositol phosphates (inositol 1-monophosphate, inositol 1,4,5,6-tetrakisphosphate, inositol 1,3,4,5,6-pentakisphosphate and inositol 1,2,3,4,5,6-hexakisphosphate), tested in vitro, did not significantly influence LH release. In saponin-permeabilized cells, the rate of basal and stimulated LH release was twice that in non-permeabilized cells. Penetration of inositol bisphosphate and inositol trisphosphate into saponin-treated pituitary cells did not increase the secretory potency of these agents compared with their effect on non-permeabilized cells. The new findings document that inositol trisphosphate formation occurs within 5-45 s after GnRH (10(-7) mol/l) administration and seems to be involved in mediating the rapid, first phase of LH release, whereas inositol bisphosphate formation occurs after 3-15 min and is probably related to later phases of LH secretion. Our results suggest that inositol bisphosphate and inositol trisphosphate are important regulators of the release of luteinizing hormone and can exert their effects not only intracellularly, but also extracellularly.

Animals↗