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At least 865 records · Page 48Linked to original sources
PubMed2001

Chronic inositol increases striatal D(2) receptors but does not modify dexamphetamine-induced motor behavior. Relevance to obsessive-compulsive disorder.

A large body of evidence suggests that the neuropathology of obsessive-compulsive disorder (OCD) lies in the complex neurotransmitter network of the cortico-striatal-thalamo-cortical (CSTC) circuit, where dopamine (DA), serotonin (5HT), glutamate (Glu), and gamma-amino butyric acid (GABA) dysfunction have been implicated in the disorder. Chronic inositol has been found to be effective in specific disorders that respond to selective serotonin reuptake inhibitors (SSRIs), including OCD, panic, and depression. This selective mechanism of action is obscure. Since nigro-striatal DA tracts are subject to 5HT(2) heteroreceptor regulation, one possible mechanism of inositol in OCD may involve its effects on inositol-dependent receptors, especially the 5HT(2) receptor, and a resulting effect on DA pathways in the striatum. In order to investigate this possible interaction, we exposed guinea pigs to oral inositol (1.2 g/kg) for 12 weeks. Subsequently, effects on locomotor behavior (LB) and stereotype behavior (SB), together with possible changes to striatal 5HT(2) and D(2) receptor function, were determined. In addition, the effects of chronic inositol on dexamphetamine (DEX)-induced motor behavior were evaluated. Acute DEX (3 mg/kg, ip) induced a significant increase in both SB and LB, while chronic inositol alone did not modify LA or SB. The behavioral response to DEX was also not modified by chronic inositol pretreatment. However, chronic inositol induced a significant increase in striatal D(2) receptor density (B(max)) with a slight, albeit insignificant, increase in 5HT(2) receptor density. This suggests that D(2) receptor upregulation may play an important role in the behavioral effects of inositol although the role of the 5HT(2) receptor in this response is questionable.

Animals↗
PubMed2001

The antidepressant activity of inositol in the forced swim test involves 5-HT(2) receptors.

The effect of inositol as an antidepressant was previously demonstrated in both animal models of depression-like behavior and in clinical trials. Unlike most antidepressant drugs, inositol does not have a clear target in the synapse and was not demonstrated to alter monoamine levels in the brain. The present study attempted to draw a psychopharmacological profile of inositol's behavioral effects by exploring the interactions between the drug and specific receptor agonists and antagonists in the forced swim test. Rats received inositol treatment (or control) in combination with the serotonergic metabolism inhibitor PCPA or with the noradrenergic neurotoxin DSP-4. Results indicated that PCPA but not DSP-4 abolished the ability of inositol to cause a reduction in immobility time in the forced swim test. In mice, the specific 5-HT(2A)/5-HT(2C) antagonist ritanserin, but not the 5-HT(1A)/5-HT(1B)/beta adrenergic antagonist pindolol, abolished inositol's effect in the forced swim test. The 5-HT(2A)/5-HT(2C) agonist DOI and the 5-HT(1A) agonist 8-OH-DPAT did not have any significant effects on inositol's activity. The present data indicates that the antidepressant effect of inositol may involve 5-HT(2) receptors. It is thus possible that the effects of reuptake antidepressant drugs and the effects of inositol may have a common final pathway.

Animals↗
PubMed2001

Differential neuronal localizations and dynamics of phosphorylated and unphosphorylated type 1 inositol 1,4,5-trisphosphate receptors.

Type 1 inositol 1,4,5-trisphosphate receptors are phosphorylated by cyclic-AMP-dependent protein kinase A at serines 1589 and 1755, with serine 1755 phosphorylation greatly predominating in the brain. Inositol 1,4,5-trisphosphate receptor protein kinase A phosphorylation augments Ca(2+) release. To assess type 1 protein kinase A phosphorylation dynamics in the intact organism, we developed antibodies selective for either serine 1755 phosphorylated or unphosphorylated species. Immunohistochemical studies reveal marked variation in localization. For example, in the hippocampus the phosphorylated type 1 inositol 1,4,5-trisphosphate receptor is restricted to CA1, while the unphosphorylated receptor occurs ubiquitously in CA1-CA3 and dentate gyrus granule cells. Throughout the brain the phosphorylated type 1 inositol 1,4,5-trisphosphate receptor is selectively enriched in dendrites, while the unphosphorylated receptor predominates in cell bodies. Focal cerebral ischemia in rats and humans is associated with dephosphorylation of type 1 inositol 1,4,5-trisphosphate receptors, and glutamatergic excitation of cerebellar Purkinje cells mediated by ibogaine elicits dephosphorylation of type 1 inositol 1,4,5-trisphosphate receptors that precedes evidence of excitotoxic neuronal degeneration. We have demonstrated striking variations in regional and subcellular distribution of inositol 1,4,5-trisphosphate receptor phosphorylation that may influence normal physiological intracellular Ca(2+) signaling in rat and human brain. We have further shown that the subcellular distribution of inositol 1,4,5-trisphosphate receptor phosphorylation in neurons is regulated by excitatory neurotransmission, as well as excitotoxic insult and neuronal ischemia-reperfusion. Phosphorylation dynamics of type 1 inositol 1,4,5-trisphosphate receptors may modulate intracellular Ca(2+) release and influence the cellular response to neurotoxic insults.

Adult↗
PubMed2004

Studies of myo-inositol and plasmalogen metabolism in rat brain.

Plasmalogens are ether-linked phospholipids that are abundant in nervous tissues. Their biological role is unclear, but may involve membrane structure/function and antioxidant activities. This study further investigates a recent report that chronic administration of myo-inositol in rats increased brain phosphatidylethanolamine plasmalogen (PlsEtn). We examined the effects of myo-inositol administration on the incorporation of [2-(13)C]ethanolamine ([2-(13)C]Etn) into rat brain phospholipids using NMR spectroscopy. Rats received either acute myo-inositol (single dose) +/- [2-(13)C]Etn, or chronic myo-inositol (10-day treatment) + [2-(13)C]Etn. Controls received saline rather than myo-inositol. Acute myo-inositol produced a 68% increase in brain [myo-inositol] and an increase in the incorporation of [2-(13)C]Etn into phospholipids (P < .05). The PlsEtn/phosphatidylethanolamine ratio and the [PlsEtn] were increased by 27% and 30%, respectively. The PlsEtn content as a mole percentage of total phospholipids was elevated (P < or = .05). Acute administration of myo-inositol + ethanolamine illustrates a positive correlation between the brain [myo-inositol] and the biosynthesis of ethanolamine phospholipids, with preferential synthesis of PlsEtn.

Animals↗
PubMed2000

Inositol as an add-on treatment for bipolar depression.

OBJECTIVE: Inositol is a constituent of the intracellular phosphatidyl inositol (PI) second messenger system, which is linked to various neurotransmitter receptors. Inositol crosses the blood-brain barrier in pharmacological doses, and has shown efficacy in a small double-blind study of unipolar depression. This pilot study evaluated its potential efficacy and safety in bipolar depression. METHODS: Twenty-four consenting adult men and women with DSM-IV bipolar depression (bipolar I = 21; bipolar II = 3) were randomly assigned to receive either 12 g of inositol or D-glucose as placebo for 6 weeks. Efficacy and safety ratings were done weekly. Thymoleptic medications (lithium, valproate, carbamazepine) in stable doses and at therapeutic levels at study entry were continued unchanged. RESULTS: Two subjects receiving placebo dropped out early due to worsening or non-adherence to the protocol. Among the 22 subjects who completed the trial, six (50%) of the inositol-treated subjects responded with a 50% or greater decrease in the baseline Hamilton Depression Rating Scale (HAM-D) score and a Clinical Global Improvement (CGI) scale score change of 'much' or 'very much' improved, as compared to three (30%) subjects assigned to placebo, a statistically nonsignificant difference. On the Montgomery-Asberg Depression Rating Scale (MADRS), eight (67%) of twelve inositol-treated subjects had a 50% or greater decrease in the baseline MADRS scores compared to four (33%) of twelve subjects assigned to placebo (p = 0.10). Inositol was well tolerated with minimal side effects, and thymoleptic blood levels were unaltered. CONCLUSIONS: These pilot data suggest a controlled study with an adequate sample size, and the appropriate rating scale may demonstrate efficacy for inositol in bipolar depression. The tolerability and the 'natural substance' aspect of inositol may be particularly appealing to subjects with bipolar depression.

Adult↗
PubMed1986

Specificity of inositol phosphate-stimulated Ca2+ mobilization from Swiss-mouse 3T3 cells.

Pure samples of inositol 1,3,4-trisphosphate, inositol 1,3,4,5-tetrakisphosphate and inositol 1,2-cyclic 4,5-trisphosphate were prepared and tested for their ability to mobilize calcium from intracellular stores in a permeabilized Swiss mouse 3T3 cell preparation. In this system inositol 1,4,5-trisphosphate mobilizes Ca2+ with a half-maximal dose of 0.3 microM. Inositol 1,2-cyclic 4,5-trisphosphate mobilized Ca2+ to the same extent with a half-maximal dose of 0.3 microM, whereas inositol 1,3,4-trisphosphate required a half-maximal dose of approx. 9 microM to give the same effect. Inositol 1,3,4,5-tetrakisphosphate was ineffective up to 20 microM and at that concentration did not antagonize the mobilization induced by inositol 1,4,5-trisphosphate. The relevance of these findings to the function of the inositol tris/tetrakis-phosphate pathway is discussed.

Animals↗
PubMed1987

Adrenergic regulation of formation of inositol phosphates in rat submandibular acini.

Formation of inositol phosphates in response to adrenergic secretagogues was studied in rat submandibular acini labelled with myo-[2-3H]inositol. Noradrenaline rapidly (within 5 s) increased radioactivity incorporated into inositol 1,4,5-trisphosphate and inositol tetrakisphosphate, with less rapid (within 1 min) increases in inositol 1,3,4-trisphosphate being observed. Inositol polyphosphate formation was less sensitive to noradrenaline than was stimulation of mucin secretion and was mediated by stimulation of alpha- but not beta-adrenergic receptors. The beta-adrenergic agonist isoproterenol, which is a potent stimulator of mucin secretion [McPherson & Dormer (1984) Biochem. J. 224, 473-481] did not increase formation of inositol mono-, bis- or polyphosphates during a 15 min incubation. The results suggest that inositol phosphates do not mediate beta-adrenergic stimulation of mucin secretion in rat submandibular acini. In addition, rat submandibular acinar cells contain a Ca2+ pool which can be mobilized by isoproterenol [McPherson & Dormer (1984) Biochem. J. 224, 473-481], without involvement of inositol polyphosphates as second messengers.

Animals↗
PubMed1987

Inositol phosphate metabolism in bradykinin-stimulated human A431 carcinoma cells. Relationship to calcium signalling.

Stimulation of human A431 epidermoid carcinoma cells by bradykinin causes a very rapid release of inositol phosphates and a transient rise in cytoplasmic free Ca2+ concentration ([Ca2+]i). Bradykinin-induced inositol phosphate formation is half-maximal at a concentration of 4 nM and is not affected by pertussis toxin. H.p.l.c. analysis of the various inositol phosphates shows an immediate but transient accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], which reaches a peak value of approx. 10 times the basal level within 15 s and slightly precedes the rise in [Ca2+]i, both parameters changing in parallel. After a lag period, bradykinin also induces a massive accumulation of Ins(1,3,4)P3 and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4]. Our data support the view that part of the newly formed Ins(1,4,5)P3 is converted into Ins(1,3,4)P3 phosphorylation/dephosphorylation with Ins(1,3,4,5)P4 as intermediate. Furthermore, A431 cells were found to contain strikingly high basal levels of two other inositol phosphates, presumably inositol pentakisphosphate (InsP5) and inositol hexakisphosphate (InsP6), representing more than 50% of the total 3H radioactivity incorporated into inositol phosphates. The presumptive InsP5 and InsP6 are only slightly affected by bradykinin. Although Ins(1,3,4)P3 and InsP4 could function as second messengers, our results suggest that, unlike Ins(1,4,5)P3, neither Ins(1,3,4)P3 nor InsP4 are involved in Ca2+ mobilization.

Bradykinin↗
PubMed1987

H.p.l.c. analysis of inositol monophosphate isomers formed on angiotensin II stimulation of rat adrenal glomerulosa cells.

[3H]Inositol-prelabelled isolated rat adrenal glomerulosa cells were stimulated with 25 nM-AII ([Asp1, Ile5]-angiotensin II) in the presence of 10 mM-Li+, and the resulting inositol monophosphate isomers were separated successfully by using a recently developed h.p.l.c. methodology. Two major peaks of radioactivity were detected which showed the same retention characteristics on h.p.l.c. as inositol 4-phosphate and inositol 1-phosphate and which increased 5-fold and 8-fold respectively on stimulation with AII. In addition, a relatively small peak with the retention characteristics of inositol 1:2-cyclic phosphate was seen to undergo a 1.5-fold increase on stimulation. This was not considered sufficient to suggest that cyclic phosphoinositols were a major product of AII-stimulated phosphoinositide turnover. No peaks of radioactive material were detected in the regions expected for inositol 2-phosphate (an acid hydrolysis product of inositol 1:2-cyclic phosphate) or inositol 5-phosphate. These results establish the identity of the major inositol phosphate products in AII-stimulated glomerulosa cells and confirm and extend the previous observations of Balla, Baukal, Guillemette, Morgan & Catt [(1986) Proc. Natl. Acad. Sci. 83, 9323-9327].

Adrenal Glands↗
PubMed1987

Formation of inositol phosphate isomers in GH3 pituitary tumour cells stimulated with thyrotropin-releasing hormone. Acute effects of lithium ions.

With a h.p.l.c. system, the inositol mono-, bis- and tris-phosphate isomers found in [3H]inositol-labelled GH3 cells were resolved and identified. These cells possess at least ten distinct [3H]inositol-containing substances when acid-soluble extracts are analysed by anion-exchange h.p.l.c. These substances were identified by their co-elution with known inositol phosphate standards and, to a limited extent, by examining their chemical structure. Two major inositol monophosphate (InsP) isomers were identified, namely Ins1P and Ins4P, both of which accumulate after stimulation with the hypothalamic releasing factor (TRH) (thyrotropin-releasing hormone). Three inositol bisphosphate (InsP2) isomers were resolved, of which two were positively identified, i.e. Ins(1,4)P2 and Ins(3,4)P2. TRH treatment increases both of these isomers, with Ins(1,4)P2 being produced at a faster rate than Ins(3,4)P2. The third InsP2 isomer has yet to be fully identified, although it is co-eluted with an Ins(4,5)P2 standard. This third InsP2 is also increased after TRH stimulation. In common with other cell types, the GH3 cell contains two inositol trisphosphate (InsP3) isomers: Ins(1,4,5)P3, which accumulates rapidly, and Ins(1,3,4)P3, which is formed more slowly. The latter substance appears simultaneously with its precursor, inositol 1,3,4,5-tetrakisphosphate. We also examined the effects of acute Li+ treatment on the rates of accumulation of these isomers, and demonstrated that Li+ augments TRH-mediated accumulation of Ins1P, Ins4P, Ins(1,4)P2, the presumed Ins(4,5)P2 and Ins(1,3,4)P3. These results suggest that the effects of Li+ on inositol phosphate metabolism are more complex than was originally envisaged, and support work carried out by less sophisticated chromatographic analysis.

Chromatography, High Pressure Liquid↗
PubMed1992

The inositol phosphates in WRK1 rat mammary tumour cells.

1. A detailed structural survey has been made of the inositol phosphates of unstimulated and vasopressin-stimulated WRK-1 rat mammary tumour cells. Inositol phosphate peaks were separated by h.p.l.c., and structural assignments were made for more than 20 compounds by combinations of: (a) co-chromatography with labelled standards; (b) site-specific enzymic dephosphorylation; (c) complete and partial periodate oxidation, followed by h.p.l.c. of polyols and their stereospecific oxidation by dehydrogenases; and (d) ammoniacal hydrolysis. 2. The 'inositol monophosphates' fraction from unstimulated cells included an uncharacterized peak, probably containing some glycerophosphoinositol, and Ins(1:2-cyclic)P. Stimulation provoked accumulation of both Ins1P and Ins3P, of Ins2P, and of Ins5P and/or the enantiomers Ins4P and Ins6P. The proportions of Ins1P and Ins3P were determined by partial periodate oxidation and enantiomeric identification of the resulting glucitols. 3. Three inositol bisphosphate peaks were detected in unstimulated cells: Ins(1,4)P2 [this was distinguished chemically from its enantiomer Ins(3,6)P2], Ins(3,4)P2 and/or Ins(1,6)P2, and Ins(4,5)P2 and/or Ins(5,6)P2. On stimulation, Ins(1,4)P2 and Ins(3,4)P2 [and/or Ins(1,6)P2] levels increased, and Ins(1:2-cyclic,4)P2 and Ins(1,3)P2 were also formed. 4. Three inositol trisphosphate peaks were obtained from unstimulated cells: all increased during stimulation. These were Ins(1,3,4)P3 [with some Ins(1:2-cyclic,4,5)P3], Ins(1,4,5)P3 and Ins(3,4,5)P3 [and/or Ins(1,5,6)P3]. During stimulation, another compound, probably Ins(1,4,6)P3, appeared in the 'Ins(1,4,5)P3 peak'. The 'Ins(3,4,5)P3 peak' contained a second trisphosphate, probably Ins(2,4,5)P3. 5. Three inositol tetrakisphosphates, namely Ins(1,3,4,6)P4, Ins(1,3,4,5)P4, were present in unstimulated cells, and all accumulated during stimulation. 6. Ins(1,3,4,5,6)P5, which is the most abundant inositol polyphosphate in these cells, a less abundant inositol pentakisphosphate and inositol hexakisphosphate were all unresponsive to stimulation.

Animals↗
PubMed1993

The characteristics, capacity and receptor regulation of inositol uptake in 1321N1 astrocytoma cells.

The uptake of inositol into 1321N1 astrocytoma cells was studied by measurement of the accumulation of free [3H]inositol within the intracellular pool. Uptake occurs via a saturable transporter with apparent Km for inositol approximately 40 microM and Vmax approximately 180 pmol/min per mg of protein, which permits intracellular inositol concentrations to exceed those of the medium by a factor of approximately 500. At extracellular concentrations up to 500 microM, inositol uptake is highly dependent (> or = 85%) on the presence of Na+ in the medium, and at physiological extracellular inositol concentrations, allows inositol to achieve an intracellular concentration of approximately 20 mM, indicating an active process driven by the Na+ gradient. Despite this, uptake was only minimally impaired or was unaffected by ouabain (1 mM) or dinitrophenol (1 mM). Consistent with a carrier-mediated mechanism, uptake was competitively blocked by phlorhizin (K1 approximately 125 microM). Uptake was also inhibited by carbachol and histamine, which act respectively via muscarinic and H1 receptors in these cells to stimulate phospholipase C. Inhibition by carbachol was dose-dependent (EC50 approximately 3-30 microM) and blocked by atropine. Inhibition by carbachol (1 mM) was non-competitive, resulting from approximately 50% decrease in the Vmax for uptake without affecting the Km and was persistent over 30-90 min. Inhibition by carbachol and histamine was independent of extracellular Ca2+ and was reproduced by phorbol ester, but not by Ca2+ ionophore or stimulation of adenylate cyclase. These results imply that receptors which couple to phospholipase C may mediate inhibition of inositol uptake via protein kinase C. The data are discussed in relation to inositol homoeostasis in resting and stimulated cells.

Astrocytoma↗
PubMed1999

Effect of aldose reductase inhibitors on glucose-induced changes in sorbitol and myo-inositol metabolism in human neutrophils.

AIM: To investigate the influence of glucose and the efficacy of two different aldose reductase (AR) inhibitors, epalrestat and SNK-860, on the polyol pathway and myo-inositol metabolism in human neutrophils. METHODS: We incubated neutrophils with various concentrations of glucose and AR inhibitors. The neutrophils from healthy volunteers were incubated in the media containing 5-40 mmol/l glucose with or without an AR inhibitor. The sorbitol and myo-inositol contents, and myo-inositol uptake were measured by high performance liquid chromatography and radio isotope technique with 2-[3H]-myo-inositol. RESULTS: After 2 h incubation, the sorbitol content increased with rising extracellular glucose concentrations, while the myo-inositol content decreased. Both AR inhibitors reduced the sorbitol content in neutrophils exposed to 40 mmol/l glucose medium. A 70% fall in the myo-inositol content in neutrophils exposed to 40mmol/glucose medium was attenuated approximately 40% by the addition of AR inhibitors. myo-Inositol uptake into neutrophils was inhibited by high glucose. AR inhibitors significantly ameliorated the decrease in myo-inositol uptake, but did not completely normalize it. CONCLUSIONS: Our present in vitro studies showed that the glucose-induced metabolic alterations in human neutrophils were similar to those in tissues prone to diabetic complications, and that AR inhibitors effectively corrected glucose-induced imbalances of the polyol pathway and myo-inositol uptake in neutrophils. In addition, our study suggests that glucose-induced metabolic alterations may result in the neutrophil dysfunction and that an AR inhibitor may be capable ameliorating it.

Adult↗
PubMed2005

Inositol transport in mouse embryonic stem cells.

The uptake of myo-inositol by mouse embryonic stem (ES) cells was measured using [2-(3)H]myo-inositol. Uptake of myo-inositol by ES cells occurred in a mainly saturable, sodium-, time- and temperature-dependent manner, which was inhibited by glucose, phloridzin and ouabain. Self inhibition by inositol was much greater than inhibition by glucose indicating that transport was not occurring via a sodium-dependent glucose transporter. Uptake rate was much greater than efflux rate indicating a mainly unidirectional transport mechanism. Estimated kinetics parameters for sodium-dependent inositol uptake were a K m of 65.1 +/- 11.8 micromol L(-1) and a V max of 5.0 +/- 0.59 pmol microg protein(-1) h(-1). Inositol uptake was also sensitive to osmolality; uptake increased in response to incubation in hypertonic medium indicating a possible role for inositol as an osmolyte in ES cells. These characteristics indicate that myo-inositol transport in mouse ES cells occurs by a sodium-dependent myo-inositol transporter protein.

Animals↗
PubMed1995

Regulation of yeast phospholipid biosynthetic gene expression in response to inositol involves two superimposed mechanisms.

Transcription of phospholipid biosynthetic genes in the yeast Saccharomyces cerevisiae is maximally derepressed when cells are grown in the absence of inositol and repressed when the cells are grown in its presence. We have previously suggested that this response to inositol may be dictated by regulating transcription of the cognate activator gene, INO2. However, it was also known that cells which harbor a mutant opi1 allele express constitutively derepressed levels of target genes (INO1 and CHO1), implicating the OPI1 negative regulatory gene in the response to inositol. These observations suggested that the response to inositol may involve both regulation of INO2 transcription as well as OPI1-mediated repression. We investigated these possibilities by examining the effect of inositol on target gene expression in a strain containing the INO2 gene under control of the GAL1 promoter. In this strain, transcription of the INO2 gene was regulated in response to galactose but was insensitive to inositol. The expression of the INO1 and CHO1 target genes was still responsive to inositol even though expression of the INO2 gene was unresponsive. However, the level of expression of the INO1 and CHO1 target genes correlated with the level of INO2 transcription. Furthermore, the effect of inositol on target gene expression was eliminated by deleting the OPI1 gene in the GAL1-INO2-containing strain. These data suggest that the OPI1 gene product is the primary target (sensor) of the inositol response and that derepression of INO2 transcription determines the degree of expression of the target genes.

Base Sequence↗
PubMed1996

The effects of inositol 1,4,5-trisphosphate (InsP3) analogues on the transient kinetics of Ca2+ release from cerebellar microsomes. InsP3 analogues act as partial agonists.

An investigation of the effects of a number of inositol trisphosphate analogues on the transient kinetics of Ca2+ release from cerebellar microsomes was undertaken. All the analogues investigated could release the total Ca2+ content of the inositol 1, 4,5-trisphosphate (Ins(1,4,5)P3) mobilizable Ca2+ store; however, their potencies were substantially reduced compared to Ins(1,4,5)P3. The concentration required to induce half-maximal Ca2+ mobilization was 0.14 microM for Ins(1,4,5)P3, 1.8 microM for 3-deoxyinositol 1,4, 5-trisphosphate (3-deoxyInsP3), 1.0 microM for 2,3-dideoxyinositol 1, 4,5-trisphosphate (2,3-dideoxyInsP3), 24 microM for 2,3, 6-trideoxyinositol 1,4,5-trisphopshate (2,3,6-trideoxyInsP3), and 2.9 microM for inositol 2,4,5-trisphosphate (Ins(2,4,5)P3). In all cases and for all concentrations tested, the inositol trisphosphate analogues induced biphasic transient release of Ca2+, which could fit to a biexponential equation assuming two independent processes. The rate constants calculated for the release process were much larger for Ins(1,4,5)P3 than the other inositol trisphosphates (the fast phase rate constant varying from 0.3 to 1.6 s-1 and the slow phase from 0.01-0.5 s-1, at concentrations between 0.03 and 20 microM Ins(1,4,5)P3). The rate constants for all other inositol trisphosphates did not appear to exceed 0.4 s-1 for the fast phase and 0.1 s-1 for the slow phase at their highest concentrations tested. The maximum amplitudes for Ca2+ release by the two phases appeared to be similar for all inositol trisphosphates (approximately 45% for the fast phase and approximately 55% for the slow phase). On comparing the rate constants for Ca2+ release at inositol trisphosphate concentrations for the analogues which all induced the same extent of Ca2+ release, it was apparent that the rates of release were independent of the extent of Ca2+ release. As the extent of Ca2+ release can be related to degree of occupancy of the binding sites, it is evident that different analogues which occupy the binding site of the receptor to the same extent can induce Ca2+ to be released at different rates. We explain this conclusion in terms of partial agonism where inositol phosphates can induce two (or more) occupied states of the channel.

Animals↗
PubMed2004

myo-Inositol and sucrose concentrations affect the accumulation of raffinose family oligosaccharides in seeds.

Raffinose family oligosaccharides (RFOs) fulfil multiple functions in plants. In seeds, they possibly protect cellular structures during desiccation and constitute carbon reserves for early germination. Their biosynthesis proceeds by the transfer of galactose units from galactinol to sucrose. Galactinol synthase (GolS), which mediates the synthesis of galactinol from myo-inositol and UDP-galactose, has been proposed to be the key enzyme of the pathway. However, no significant relationship was detected between the extractable GolS activity and the amount of RFOs in seeds from seven pea (Pisum sativum L.) genotypes selected for high variation in RFO content. Instead, a highly significant correlation was found between the levels of myo-inositol and RFOs. Moderately strong relationships were also found between sucrose and RFO content as well as between myo-inositol and galactinol. Further evidence for a key role of myo-inositol for the synthesis of galactinol was obtained by feeding exogenous myo-inositol to intact pea seeds and by the analysis of four barley (Hordeum vulgare L.) low phytic acid mutants. In seeds of three of these mutants, the reduced demand for myo-inositol for the synthesis of phytic acid (myo-inositol 1,2,3,4,5,6-hexakisphosphate) was associated with an increased level in myo-inositol. The mutants seeds also contained more galactinol than wild-type seeds. The results suggest that the extent of RFO accumulation is controlled by the levels of the initial substrates, myo-inositol and sucrose, rather than by GolS activity alone.

Hordeum↗
PubMed1996

Pervanadate mediated an increased generation of inositol phosphates and tension in rat myometrium. Activation and phosphorylation of phospholipase C-gamma 1.

Stimulation of [3H]inositol-labeled rat myometrial strips with pervanadate, formed by mixing orthovanadate and H2O2, induced a dose-dependent accumulation of [3H]inositol phosphates. Orthovanadate or H2O2 added alone had no effect. Pretreatment of myometrium with two tyrosine kinase inhibitors, namely genistein and tyrphostin 47 (at 100 microM), reduced pervanadate-stimulated inositol phosphate formation by 50%. Pervanadate induced a time-sequential formation of inositol phosphates in the order inositol trisphosphate, inositol bisphosphate, and inositol monophosphate. The inhibitory effect of genistein was observed at the level of the three inositol phosphates. Pervanadate induced contraction of the myometrium; the response was dose-dependent. H2O2 or orthovanadate was without effect. Pervanadate-mediated contraction was inhibited (50%) by genistein and tyrphostin 47 (100 microM). Western blot analysis, using anti-phosphotyrosine antibodies, revealed that phosphorylated proteins were present in detergent extracts from pervanadate-stimulated myometrium. Tyrosine phosphorylation was reduced by a preincubation with 100 microM genistein or tyrphostin 47. Phospholipase C-gamma1 was immunodetected in myometrial extracts and was identified as one of the substrates subject to tyrosine phosphorylation following pervanadate treatment. The results demonstrate that, in myometrium, protein tyrosine kinase/phosphatase activities controlled both phosphorylation and activation of phospholipase C-gamma1, contributing to the modulation of the generation of inositol phosphates and tension.

Animals↗