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PubMed1997

Inositol 1,4,5-trisphosphate receptor expression in odontoblast cells.

The cellular distribution of inositol 1,4,5-trisphosphate receptors was examined in rodent maxillary incisor teeth. In situ hybridization studies with a transmembrane probe of type I inositol 1,4,5-trisphosphate receptor indicated that this receptor/channel was highly expressed in odontoblast cells of incisor teeth. In contrast, very low labeling was observed in dental pulp. Northern analysis showed a message size of approximately 9.5 kilobases for this receptor, and demonstrated that type III inositol 1,4,5-trisphosphate receptor was expressed in incisor teeth. Immunocytochemical studies confirmed that types I and III inositol 1,4,5-trisphosphate receptors were both highly expressed in odontoblasts while very low expression was detected in dental pulp. Finally, antibodies that recognized alpha subunits of the Gq class of GTP binding proteins also stained odontoblasts. These results indicate that receptor-mediated regulation of calcium release through inositol 1,4,5-trisphosphate receptors may occur in odontoblasts of rat incisor teeth. These findings also suggest that inositol 1,4,5-trisphosphate receptor/channels regulate calcium flux in odontoblasts during mineralization of dentin, or in growth and differentiation of incisor tissue.

Animals↗
PubMed2003

Are myo-inositol, glucose and zinc concentrations in amniotic fluid of fetuses with spina bifida different from controls?

OBJECTIVE: Associations are reported between myo-inositol, glucose, zinc and the occurrence of spina bifida. To gain more insight into the pathogenesis of spina bifida, the concentrations of myo-inositol, glucose and zinc were determined in amniotic fluids from pregnancies with a spina bifida or unaffected control fetus. METHODS: Amniotic fluids of 27 pregnancies complicated by spina bifida and 49 controls were collected at the Department of Obstetrics and Gynecology of the University Medical Center Nijmegen in the Netherlands. Myo-inositol, glucose and zinc concentrations were determined. By indication, the samples were taken at different gestational ages. Therefore, the data were evaluated using multiple linear regression analysis to adjust for gestational age. RESULTS: Amniocentesis was performed at a more advanced gestational age in the spina bifida group than in controls. In the spina bifida group, amniotic fluid myo-inositol, glucose and zinc concentrations gradually declined throughout pregnancy. At a gestational age of 15 weeks, the estimated mean amniotic fluid glucose and zinc concentrations in the spina bifida group were, respectively, significantly lower (p< or =0.5) and higher (p< or =0.5) compared with the control group. At the same gestational age, the estimated mean myo-inositol concentrations were comparable in both groups. At a gestational age of 38 weeks, the estimated mean myo-inositol, glucose and zinc concentrations were not significantly different in the spina bifida compared with the control group. CONCLUSION: This study may suggest that a derangement in zinc and glucose transfer or metabolism is associated with spina bifida. Since compounds in amniotic fluid are only a very crude marker of the actual fetal condition, studies that focus on the metabolism of these compounds on tissue or even cellular level should be performed to clarify their role in the pathogenesis and future prevention of spina bifida.

Adult↗
PubMedDate not supplied

Rescue of excitation by inositol following Li(+)-induced block in Limulus ventral photoreceptors.

The phosphoinositide (PI) intracellular signaling pathway, which triggers Ca2+ release from intracellular stores, appears to be a central feature of phototransduction in most invertebrate species studied. Procedures designed to inhibit PI-pathway reactions cause suppression of excitation to dim lights. However, in Limulus photoreceptors, responses to bright stimuli are in fact enhanced by some of these procedures, suggesting that PI metabolism is not obligatory for light-induced excitation. Other studies, however, suggest that Ca2+ release is obligatory for excitation. We studied this issue by examining the effects of PI-pathway inhibitor, Li+, on electrophysiological responses to light in Limulus photoreceptors. Li+ is reported to cause depletion of intracellular PI-pathway intermediate, inositol; and it offers the pharmacological advantage that its block can be bypassed by introducing exogenous inositol. Introduction of Li+ caused a very slowly developing but complete suppression of responses to dim stimuli. In contrast, Li+ caused a rapidly developing but partial suppression of responses to bright stimuli. Li(+)-induced suppression was reversed by exogenous introduction of inositol. In addition, inositol prevented Li(+)-induced suppression of excitation. Li+ enhanced light adaptation (light-induced desensitization) but slowed response deactivation, indicating a difference in the processes underlying these phenomena. Li+ slowed dark adaptation, the recovery of sensitivity following light adaptation. All of these effects were prevented or rescued by extracellularly applied inositol, suggesting the presence of a transmembrane inositol transport system. The overall results suggest that PI-dependent signaling is central and obligatory for excitation in Limulus, at least for responses to dim to moderate illumination. The failure of Li+ to suppress bright light-induced excitation completely may be due to a failure of Li+ to block PI metabolism completely, as in other systems; however, it may point to a parallel, PI-independent excitation pathway possessing very low light sensitivity when PI metabolism is inhibited.

Adaptation, Ocular↗
PubMed2001

Stereospecificity of myo-inositol hexakisphosphate dephosphorylation by a phytate-degrading enzyme of baker's yeast.

During food processing such as baking, phytate is dephosphorylated to produce degradation products, such as myo-inositol pentakis-, tetrakis-, tris-, bis-, and monophosphates. Certain myo-inositol phosphates have been proposed to have positive effects on human health. The position of the phosphate groups on the myo-inositol ring is thereby of great significance for their physiological functions. Using a combination of high-performance ion chromatography analysis and kinetic studies the stereospecificity of myo-inositol hexakisphosphate dephosphorylation by a phytate-degrading enzyme from baker's yeast (Saccharomyces cerevisiae) was established. The data demonstrate that the phytate-degrading enzyme from baker's yeast dephosphorylates myo-inositol hexakisphosphate in a stereospecific way by sequential removal of phosphate groups via D-Ins(1,2,4,5,6)P(5), D-Ins(1,2,5,6)P(4), D-Ins(1,2,6)P(3), D-Ins(1,2)P(2), to finally Ins(2)P (notation 3/4/5/6/1). Knowledge of the absolute stereochemical specificity of the baker's yeast phytase allows use of the enzyme to produce defined myo-inositol phosphates for kinetic and physiological studies.

6-Phytase↗
PubMed2004

Determination of phytic acid and inositol pentakisphosphates in foods by high-performance ion chromatography.

A high-performance anion exchange chromatographic method was adapted for the quantitative determination of phytic acid and inositol pentakisphosphate isomers (excluding enantiomers) in foods. Because of the cost and limited availability of inositol phosphate standards, a phytic acid sodium salt standard was used for the calculation of an average relative response factor for the quantification of inositol pentakisphosphate isomers, and the purity of phytic acid sodium salt standard was also accurately established. The detection limits (S/N = 3) for phytic acid and inositol pentakisphosphates were in the range of 1.5-3.4 microM (0.1-0.2 microg/100 microL). This method has been successfully applied to the determination of phytic acid and inositol pentakisphosphates in a variety of beans and nuts after extraction with 0.5 M HCl and cleanup with solid phase extraction cartridges. The results demonstrated that there was a strong correlation between either the phytic acid content or the total content of phytic acid together with inositol pentakisphosphates and the total dietary fiber content in the group of all raw dry beans and in the group of raw dry black beans but not in the group of raw dry red kidney beans, which was probably due to the insufficient number of the raw dry red kidney bean samples.

Chromatography, High Pressure Liquid↗
PubMed1999

Inositol phosphates influence iron uptake in Caco-2 cells.

Phytate, inositol hexaphosphate (InsP(6)), may be hydrolyzed to inositol phosphates with lower degree of phosphorylation, i.e., inositol penta- to monophosphates (InsP(5)-InsP(1)), during food processing. Each of these lower inositol phosphates exists in different isomeric forms. The objective of this study was to determine if different isomers of InsP(3)-InsP(5) (Ins(1,2,4)P(3), Ins(1,2,3)P(3), Ins(1,2,6)P(3), Ins(1,3,4)P(3), Ins(1,2,3,4)P(4), Ins(1,2,5,6)P(4), Ins(1,2,4,5,6)P(5), and Ins(1,3,4,5,6)P(5)) and InsP(6) affect the uptake of iron. We studied the iron absorption in vitro using the human intestinal epithelial cell line, Caco-2. Addition of a 2-fold molar excess of InsP(6) or InsP(5) in proportion to Fe (1 h incubation at 37 degrees C) reduced iron uptake by 46-52% (p < 0.001). Neither InsP(4) isomers nor InsP(3) isomers affected iron uptake significantly at 1 h incubation with a molar InsP:Fe level of 2:1. Iron uptake was shown to not be a function of the isomeric form of inositol phosphates. The inositol phosphate isomers did not seem likely to interact with each other through iron to form more stable iron complexes. At a molar InsP:Fe level of 20:1 an inhibitory effect of InsP(4) was found, while InsP(3) did not affect the iron absorption even at a 20-fold molar excess.

Biological Transport↗
PubMed1999

Quantification of inositol phosphates using (31)P nuclear magnetic resonance spectroscopy in animal nutrition.

A (31)P NMR method for quantitative determination of inositol phosphates in simple incubation samples of sodium phytate and Aspergillus niger phytase and in different types of complex samples, such as diets, digesta, and feces, is described. The inositol phosphates in complex samples were extracted with HCl, concentrated, and purified using freeze-drying and filtration and subsequently determined at pH 12.6 in aqueous solution using a (31)P NMR method. The (31)P NMR technique has as its main advantages over the HPLC techniques that it does not necessitate standards that may cause background matrix effects and that the spectra of inositol phosphates and orthophosphate appear in the same run without further sampling errors. The results of inositol hexaphosphate analysis with HPLC can be confirmed by this (31)P NMR method. Contents of inositol tetra-, tri-, di-, and monophosphate in the biological samples appear to be quantitatively not important. The (31)P NMR method can be applied for use in animal nutrition in general and studies of using phytase in diets for farm animals in particular, by measuring the content of inositol phosphates in feed ingredients, complete feeds, ileal contents, and feces of pigs and poultry.

Animal Feed↗
PubMed2003

Isolation, structure, synthesis, and bioactivity of a novel putative insulin mediator. A galactosamine chiro-inositol pseudo-disaccharide Mn2+ chelate with insulin-like activity.

We isolated from beef liver a putative insulin mediator termed INS-2, 1. Its structure was determined to be a novel inositol glycan pseudo-disaccharide Mn(2+) chelate containing D-chiro-inositol 2a (as pinitol) and galactosamine. Purification methods were scaled up from those previously reported to isolate an inositol glycan with similar composition from rat liver.(1) Structure of the beef liver glycan was determined by degradative chemistry and 2D NMR spectroscopy and confirmed by chemical synthesis. Its structure is 4-O-(2-amino-2-deoxy-beta-D-galactopyranosyl)-3-O-methyl-D-chiro-inositol 1 (INS-2, Figure 1). Its role as an insulin mimetic was demonstrated by its action in vivo to decrease elevated blood glucose injected to low-dose streptozotocin diabetic rats in a stereospecific and dose-dependent manner. The pseudo-disaccharide also stimulated [(14)C]glucose incorporation into [(14)C]glycogen in a dose-dependent manner in H4IIE hepatoma cells in the presence of insulin, thus enhancing insulin action. Only when chelated to Mn(2+) did it activate pyruvate dehydrogenase phosphatase in vitro in a dose-dependent manner. To our knowledge, this is the first example of a beta-1,4-linked inositol glycan consisting of D-chiro-inositol and galactosamine isolated from animal tissues with insulin mimetic actions.

Animals↗
PubMed2000

Regulation of Myo-inositol homeostasis in differentiated human NT2-N neurons.

We have investigated the possible role of second messengers on inositol homeostasis in NT2-N cells, human central nervous system neurons obtained by terminal differentiation of teratocarcinoma precursors. Uptake of inositol into NT2-N neurons was inhibited approximately 10% by protein kinase C (PKC) activation but was unaffected by either the presence of cyclic nucleotide analogs or changes in the intracellular concentration of Ca2+. Efflux of inositol from NT2-N neurons was enhanced in hypotonic buffer but virtually eliminated by inclusion of the Cl- channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, a result which indicates the involvement of a volume-sensitive organic osmolyte-anion channel. Volume-sensitive inositol efflux was stimulated approximately 30% following activation of PKC or elevation of the cytosolic Ca2+ concentration but was unaffected by protein kinase A activation. These results suggest that whereas inositol uptake into NT2-N neurons is relatively refractory to regulation, volume-sensitive inositol efflux may be significantly affected by intracellular signaling events.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Ts65Dn mouse, a Down syndrome model, exhibits elevated myo-inositol in selected brain regions and peripheral tissues.

myo-Inositol is elevated in the Down syndrome (DS; trisomy 21) brain and may play a role in mental retardation. In the present study, we examined brain regions and peripheral tissues of Ts65Dn mouse, a recently characterized genetic model of DS, for abnormal myo-inositol accumulation. A GC/MS technique was used to quantitate myo-inositol and other polyol species (ribitol, arabitol, xylitol, and 1,5-anhydrosorbitol) in tissues from the Ts65Dn mice and control diploid mice. myo-Inositol was found to be elevated in frontal cortex, hippocampus, and brain stem but not in cerebellum of the Ts65Dn mouse. Among peripheral organs examined, liver and skeletal muscle were found to excessively accumulate myo-inositol. In all tissues, concentrations of polyol internal controls were normal. The Ts65Dn mouse is useful to study the possible effect of elevated myo-inositol on cellular processes.

Animals↗
PubMed2004

An optimized fixation and extraction technique for high resolution of inositol phosphate signals in rodent brain.

Members of lower and higher inositol phosphates distinctly participate in signal transduction (1). Relatively little is known regarding possible biological functions of inositol phosphates in functionally different areas of the intact brain. A detailed study on the regional distribution of biologically important inositol phosphates may help elucidate their physiological functions in different brain regions in the regional tissue context. We now show a novel technique which allows fixation and subsequent dissection of whole rat brains into small volume elements for mapping of the whole range of inositol phosphates from Ins(1,4,5)P3 to InsP6. The method has been successfully applied to investigate regional differences of a broader spectrum of inositol phosphates in microdissected brain tissue and to construct 3D-maps of these signaling compounds. The technique can be particularly well employed to investigate regional changes in the spectrum of higher inositol phosphates and phosphoinositides upon neuronal stimulation induced by motor activity or drug treatment.

Animals↗
PubMed1997

Lithium-induced inositol depletion in rat brain after chronic treatment is restricted to the hypothalamus.

The influence of acute and chronic lithium administration on inositol content was examined in five different regions of the rat brain: caudate, cerebellum, cortex, hippocampus and hypothalamus. After acute administration of lithium at doses of 3, 6 or 10 mEq kg-1, no significant reductions of inositol were found in any brain region. Also no significant changes were observed in cortex, caudate, hippocampus and cerebellum after chronic treatment with lithium-containing diet, which led to brain concentrations of lithium in the therapeutic range. However, a moderate but significant reduction of inositol was under these conditions observed in the hypothalamus. At basal conditions, ie in control rats not treated with lithium, the inositol content in various brain areas was different, the hypothalamus containing the highest inositol concentration (4.4 mmol kg-1 wet weight) and the cortex the lowest (2.3 mmol kg-1 wet weight). It is concluded that chronic lithium treatment at therapeutically relevant brain concentrations does not evoke major changes in the inositol content of the brain but induces a moderate decrease which is restricted to the hypothalamus. The results are discussed with respect to the potential function of the hypothalamus in affective disorders.

Animals↗
PubMed1983

Transport of myo-inositol into endoneurial preparations of sciatic nerve from normal and streptozotocin-diabetic rats.

myo-Inositol transport by a viable rat sciatic-nerve preparation is described. Such 'endoneurial' nerve preparations accumulated myo-inositol by an energy-dependent saturable system. Streptozotocin-diabetes reduced myo-inositol transport into sciatic nerve by approx. 40%. Elevated medium glucose concentration reduced myo-inositol transport into control nerves to a similar extent. Fructose and sorbitol did not inhibit myo-inositol transport. Inclusion of an aldose reductase inhibitor in the medium counteracted the reduced myo-inositol transport caused by elevated glucose concentration. The importance of these results to the problem of diabetic neuropathy is discussed.

Adenosine Triphosphate↗
PubMed1984

Rapid accumulation of inositol phosphates in isolated rat superior cervical sympathetic ganglia exposed to V1-vasopressin and muscarinic cholinergic stimuli.

An accumulation of 3H-labelled inositol phosphates is observed when prelabelled rat superior cervical sympathetic ganglia are exposed to [8-arginine]vasopressin or to muscarinic cholinergic stimuli. The response to vasopressin is much greater than the response to cholinergic stimuli. The response to vasopressin is blocked by a V1-vasopressin antagonist, and oxytocin is a much less potent agonist than vasopressin. Vasopressin causes no increase in the cyclic AMP content of ganglia. These ganglia therefore appear to have functional V1-vasopressin receptors that are capable of activating inositol lipid breakdown, but no V2-receptors coupled to adenylate cyclase. The first [3H]inositol-labelled products to accumulate in stimulated ganglia are inositol trisphosphate and inositol bisphosphate, suggesting that the initiating reaction in stimulated inositol lipid metabolism is a phosphodiesterase-catalysed hydrolysis of phosphatidylinositol 4,5-bisphosphate (and possibly also phosphatidylinositol 4-phosphate). This response to exogenous vasopressin occurs in ganglia incubated in media of reduced Ca2+ concentration. The physiological functions of the V1-vasopressin receptors of these ganglia remain unknown.

Animals↗
PubMed1985

Guanine nucleotides stimulate production of inositol trisphosphate in rat cortical membranes.

The guanine nucleotides guanosine 5'[beta, gamma-imido]triphosphate (Gpp[NH]p), guanosine 5'-[gamma-thio]-triphosphate (GTP gamma S), GMP, GDP and GTP stimulated the hydrolysis of inositol phospholipids by a phosphodiesterase in rat cerebral cortical membranes. Addition of 100 microM-Gpp[NH]p to prelabelled membranes caused a rapid accumulation of [3H )inositol phosphates (less than 30 s) for up to 2 min. GTP gamma S and Gpp [NH]p caused a concentration-dependent stimulation of phosphoinositide phosphodiesterase with a maximal stimulation of 2.5-3-fold over control at concentrations of 100 microM. GMP was as effective as the nonhydrolysable analogues, but much less potent (EC50 380 microM). GTP and GDP caused a 50% stimulation of the phospholipase C at 100 microM and at higher concentrations were inhibitory. The adenine nucleotides App[NH]p and ATP also caused small stimulatory effects (64% and 29%). The guanine nucleotide stimulation of inositide hydrolysis in cortical membranes was selective for inositol phospholipids over choline-containing phospholipids. Gpp[NH]p stimulated the production of inositol trisphosphate and inositol bisphosphate as well as inositol monophosphate, indicating that phosphoinositides are substrates for the phosphodiesterase. EGTA (33 microM) did not prevent the guanine nucleotide stimulation of inositide hydrolysis. Calcium addition by itself caused inositide phosphodiesterase activation from 3 to 100 microM which was additive with the Gpp[NH]p stimulation. These data suggest that guanine nucleotides may play a regulatory role in the modulation of the activity of phosphoinositide phosphodiesterase in rat cortical membranes.

Adenine Nucleotides↗
PubMed1987

Subsecond and second changes in inositol polyphosphates in GH4C1 cells induced by thyrotropin-releasing hormone.

It has been demonstrated previously that thyrotropin-releasing hormone (TRH) induces changes in inositol polyphosphates in the GH3 and GH4C1 strains of rat pituitary cells within 2.5-5.0 s. TRH also causes a rapid rise in cytosolic free calcium concentration ([Ca2+]i) in these cells which is due largely to redistribution of cellular calcium stores. Therefore, it has been concluded that TRH acts to release sequestered calcium in these cells via enhanced generation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. If this conclusion were correct, TRH-enhanced accumulation of Ins(1,4,5)P3 should occur at least as rapidly as the increase in [Ca2+]i. We have shown previously that the rise in [Ca2+]i induced by TRH occurs within about 400 ms; thus, it was important to investigate the subsecond time-course of changes in inositol phosphates caused by TRH. Using a rapid mixing device, we have measured changes in inositol polyphosphates on a subsecond time scale in GH4C1 cells prelabelled with myo-[2-3H]inositol. Although TRH did alter inositol polyphosphate metabolism within 500 ms, the changes observed did not reveal a statistically significant increase in Ins(1,4,5)P3 within time intervals of less than 1000 ms. Thus, we have been unable to demonstrate that a TRH-induced rise in Ins(1,4,5)P3 precedes or occurs concomitantly with the rise in [Ca2+]i in GH4C1 cells. Although these results do not disprove the current view that Ins(1,4,5)P3 mediates the action of TRH on intracellular calcium redistribution, we conclude that caution should be exercised in this, and possibly other cell systems, in accepting the dogma that all of the rapid, agonist-induced redistributions of intracellular calcium are mediated by Ins(1,4,5)P3.

Animals↗
PubMed1988

Activation of sea urchin eggs by inositol phosphates is independent of external calcium.

We investigated the contribution of external calcium ions to inositol phosphate-induced exocytosis in sea urchin eggs. We show that: (a) inositol phosphates activate eggs of the sea urchin species Lytechinus pictus and Lytechinus variegatus independently of external calcium ions; (b) the magnitude and duration of the inositol phosphate induced calcium changes are independent of external calcium; (c) in calcium-free seawater, increasing the volume of inositol trisphosphate solution injected decreased the extent of egg activation; (d) eggs in calcium-free sea water are more easily damaged by microinjection; microinjection of larger volumes increased leakage from eggs pre-loaded with fluorescent dye. We conclude that inositol phosphates do not require external calcium ions to activate sea urchin eggs. This is entirely consistent with their role as internal messengers at fertilization. The increased damage caused to eggs in calcium-free seawater injected with large volumes may allow the EGTA present in the seawater to enter the egg and chelate any calcium released by the inositol phosphates. This may explain the discrepancy between this and earlier reports.

Animals↗
PubMed1989

The effect of cholera toxin on the inhibition of vasopressin-stimulated inositol phospholipid hydrolysis is a cyclic AMP-mediated event at the level of receptor binding.

Incubation of L6 skeletal myoblasts for 16 h with cholera toxin but not with pertussis toxin, led to the inhibition of inositol phosphate generation induced by subsequent exposure to vasopressin. The effects of the toxin on inositol lipid metabolism were accompanied by the total ADP-ribosylation of the available cholera-toxin substrates within the cells. Immunological analysis demonstrated that the two polypeptides modified in vivo by cholera toxin were different forms of Gs alpha (alpha subunit of Gs). No novel cholera-toxin substrate(s) were detected. The cholera-toxin-mediated inhibition of vasopressin-stimulated inositol phosphate generation could be mimicked by both forskolin and dibutyryl cyclic AMP, but not by the separated subunits of the toxin. Receptor-binding studies demonstrated that the inhibition of agonist-stimulated inositol phosphate generation was accompanied by a decrease in cell-surface vasopressin-binding sites, with no effect on the affinity of these for the hormone. We suggest that the effect of cholera toxin and agents which increase intracellular cyclic AMP on vasopressin-stimulated inositol lipid hydrolysis is an effect on receptor number, and that there is no requirement to postulate a role for a novel G-protein, which is a substrate for cholera toxin, in the regulation of inositol phospholipid metabolism.

Adenosine Diphosphate↗