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PubMed1988

Cell cycle dependence of inositol phosphate levels in neuroblastoma cells.

To investigate the timing of inositol lipid turnover in relation to the cell cycle, inositol phosphates and lipids were measured in neuroblastoma (Neuro-2A) cells that were prelabeled with [3H]inositol and synchronized by a mitotic shakeoff technique. Distinct early and late phases of inositol phosphate production were identified. The early peak occurs between the 2nd and 4th hour after mitosis near the G1/S transition. A later peak occurs around the peak of S phase (DNA synthesis) at 7-8 h after mitosis. These findings suggest that activation of phosphatidylinositol turnover generates signals that play a role in cell cycle progression.

Animals↗
PubMed1985

Activation of muscarinic and of alpha 1-adrenergic receptors on astrocytes results in the accumulation of inositol phosphates.

Astrocyte-enriched cultures prepared from the newborn rat cortex incorporated [3H]myo-inositol into intracellular free inositol and inositol lipid pools. Noradrenaline and carbachol stimulated the turnover of these pools resulting in an increased accumulation of intracellular [3H]inositol phosphates. The effects of noradrenaline and carbachol were dose-dependent and blocked by specific alpha 1-adrenergic and muscarinic cholinergic receptor antagonists, respectively. The increase in [3H]inositol phosphate accumulation caused by these receptor antagonists was virtually unchanged when cultures were incubated in Ca2+-free medium, but was abolished when EGTA was also present in the Ca2+-free medium. Cultures of meningeal fibroblasts, the major cell type contaminating the astrocyte cultures, also accumulated [3H]myo-inositol, but no increased accumulation of [3H]inositol phosphates was found in response to either noradrenaline or carbachol.

Animals↗
PubMed1991

Interactions between inositol phosphates and cytosolic free calcium following bradykinin stimulation in cultured human skin fibroblasts.

The inositol triphosphate (IP3) that results from hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) is generally accepted to be responsible for the mobilization of intracellular calcium. However, some studies suggest that low concentrations of agonists elevate cytosolic free calcium concentration ([Ca2+]i) without IP3 formation. Thus, in the present studies, a comparison of the temporal response of inositol phosphates (IP3, IP2 and IP) and [Ca2+]i to a wide range of bradykinin concentrations was used to examine the relation of these two signal transduction events in cultured human skin fibroblasts (GM3652). In addition, the effects of alterations in internal or external calcium on the response of these second messengers to bradykinin were determined. Bradykinin stimulated accumulation of inositol phosphates and a rise of [Ca2+]i in a time- and dose-dependent manner. Decreasing the bradykinin concentration from 1 microM to 0.1 microM increased the time until the IP3 peak, and when the bradykinin concentration was reduced to 0.01 microM IP3 was not detected. [Ca2+]i was examined under parallel conditions. As the bradykinin concentration was reduced from 1 microM to 0.01 microM, the time to reach the peak of [Ca2+]i increased progressively, but the magnitude of the peak was unaltered. These two second messengers were variably dependent on external calcium. Although the bradykinin-stimulated initial spike of [Ca2+]i did not depend on extracellular calcium, the subsequent sustained levels of [Ca2+]i were abolished in calcium free medium. The bradykinin-stimulated inositol phosphate formation was not dependent on the extracellular calcium nor on the elevation of [Ca2+]i that was produced with Br-A23187. These results demonstrate that bradykinin-induced IP3 formation can be independent of [Ca2+]i and of external calcium, whereas changes in [Ca2+]i are partially dependent on external calcium.

Bradykinin↗
PubMed1995

Calmodulin antagonist W7 increases inositol phosphates in insulin secreting RINm5F cells.

W7, a calmodulin antagonist, has been reported to increase cytosolic free calcium concentration [Ca2+]i in non stimulated rat insulinoma cells (RINm5F). And this effect was not due to enhanced calcium uptake. In the present study the effect of calmodulin antagonist W7 on the inositol phosphate turnover of RINm5F cells was studied. Inositol phosphates were separated using a new modified technique of anion-exchange high performance liquid chromatography (HPLC). It was observed that W7 significantly increased inositol trisphosphate and inositol bisphosphate within 5 and 15 sec, respectively. No changes of inositol phosphates were detected employing W5, a chlorine-deficient analogue of W7 without calmodulin antagonistic action. Our data are in favour of the view that (I) calmodulin may be involved in inositol phosphate metabolism of RINm5F cells and that (II) the increase of [Ca2+]i in response to W7 as reported previously may be due to elevation of inositol trisphosphate.

Animals↗
PubMed1987

Alpha 1-adrenoceptor production of inositol phosphates mediates the inhibition of thyroxine release from the mouse thyroid.

To examine the mechanism of the alpha 1-adrenoceptor-mediated inhibition of the release of thyroid hormones in the mouse thyroid, the effect of noradrenaline on the production of inositol phosphates was investigated using thyroids preloaded with [3H]inositol. Noradrenaline increased [3H]inositol accumulation into inositol phosphates in the mouse thyroid during a 30-min incubation whereas TSH (10 mU/ml) was without effect. The effect of noradrenaline was mimicked by phenylephrine, but not by clonidine or isoprenaline. Prazosin antagonized the effect of noradrenaline, while yohimbine had no effect. These results suggest that noradrenaline-induced production of inositol phosphates is mediated by alpha 1-adrenoceptors. The inhibition of release of thyroid hormones elicited by alpha 1-adrenergic agonists in the mouse thyroid is possibly mediated through the hydrolysis of membrane phosphoinositides followed by the generation of second messengers such as inositol phosphates and diacylglycerol.

Animals↗
PubMed2003

Structural distinction among inositol phosphate isomers using high-energy and low-energy collisional-activated dissociation tandem mass spectrometry with electrospray ionization.

Electrospray (ESI) collisional-activated dissociation (CAD) tandem mass spectrometric methods for the structural characterization of inositol phosphates (InsPs) using both quadrupole and sector mass spectrometers are described. Under low-energy CAD, the [M + H](+) ions of the positional isomers of inositol phosphates, including inositol mono-, bis- and trisphosphates, yield distinguishable product-ion spectra, which are readily applicable for isomer differentiation. In contrast, the product-ion spectra arising from high-energy CAD (2 keV collision energy, floating at 50%) tandem sector mass spectrometry are less applicable for isomer identification. The differences in the product-ion spectrum profiles among the aforementioned InsP isomers become more substantial and differentiation of positional isomers can be achieved when the collison energy is reduced to 1 keV (floating at 75%). These results demonstrate that the applied collision energies play a pivotal role in the fragmentations upon CAD. The product-ion spectra are similar among the positional isomers of inositol tetrakisphosphates and of inositol pentakisphosphates. Thus, isomeric distinction for these two inositol polyphosphate classes could not be established by the tandem mass spectrometric methods that have achieved such distinctions for the less highly phosphorylated inositol phosphate classes. Under both high- and low-energy CAD, the protonated molecular species of all InsPs undergo similar fragmentation pathways, which are dominated by the consecutive losses of H(2)O, HPO(3) and H(3)PO(4).

Animals↗
PubMed1999

Relationship between dopamine agonist stimulation of inositol phosphate formation and cytidine diphosphate-diacylglycerol accumulation in brain slices.

Dopamine receptor-coupled stimulation of inositol phosphate formation has been characterized extensively, but little is known about the diacylglycerol arm of this dual-signaling pathway. This study examined several parameters of cytidine diphosphate-diacylglycerol (CDP-DG) accumulation as an index of agonist-stimulated DG formation. Rat brain slices pre-labeled with 5-[3H]cytidine were incubated with various test agents in the presence of LiCl and accumulated CDP-DG analyzed. Dopamine and SKF38393 significantly and dose-dependently stimulated CDP-DG accumulation. SKF38393 responses were inhibited by neomycin and reversed by myo-inositol or by exclusion of LiCl. Compared to inositol phosphate formation in 2-[3H]inositol-prelabeled slices, the CDP-DG responses were proportionately greater, while the agonist EC50 values were similar between the two assays. The D1-receptor antagonist SCH23390 inhibited SKF38393-mediated responses at 0.1-10 microM concentrations, whereas greater concentrations reversed the inhibition. SKF38393 effects were completely blocked by the DG kinase inhibitor R59022, thus precluding any role for phospholipase-D or de novo phosphatidate synthesis in the dopaminergic response. D609 which inhibits phosphatidylcholine-specific phospholipase-C (PLC), potently inhibited both CDP-DG accumulation and inositol phosphate formation. These findings demonstrate that the selective D1-receptor antagonist SCH23390 is a partial agonist at the D1-like dopamine receptor that couples to phosphoinositide signaling, that dopaminergic facilitation of phosphoinositide signaling is independent of de novo phosphatidate synthesis, and that the widely used enzyme inhibitor, D-609, is probably not selective for phosphatidylcholine-specific PLC in brain slice preparations. The greater sensitivity of the CDP-DG measurement presents this assay as a reliable and possibly superior index of dopamine receptor-coupled PLC activation in intact tissues.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Amplification of fluoroaluminate-stimulated inositol phosphate generation in a cell line overexpressing the p21N-ras gene.

The stimulation of inositol phosphate generation in NIH-3T3 cells and a derived transformant overexpressing the p21N-ras gene (T15+ cells) was examined. Incubation with NaF in the presence of Al3+ leads to the generation of inositol phosphates in each cell type, though the response in the T15+ cells is significantly amplified. The effect of fluoroaluminate is dose- and time-dependent. No differences were observed in fluoroaluminate-stimulated cyclic AMP accumulation among the cell types. In another NIH-3T3-derived cell line that expresses the transforming lys61 mutant of N-ras, no amplification of fluoroaluminate-stimulated inositol phosphate generation is observed. These results provide support for the proposal that, in the T15 cell line, p21N-ras can act in a guanine nucleotide-binding regulatory protein (G-protein)-like manner.

Aluminum↗
PubMed1987

Inhibitory action of spermidine on formyl-methionyl-leucyl-phenylalanine stimulated inositol phosphate production in human neutrophils.

The effect of the polyamine, spermidine, on formyl-methionyl-leucyl-phenylalanine stimulated hydrolysis of polyphosphoinositides was examined in purified human neutrophils by measurement of inositol phosphate production from radioactively labelled inositol. Spermidine inhibited formyl-methionyl-leucyl-phenylalanine stimulated inositol phosphate production by neutrophil in a dose dependent manner. Inhibition of formyl-methionyl-leucyl-phenylalanine stimulated inositol phosphate accumulation by spermidine was maximal at 10 microM and the IC50 value for this effect was 4.2 microM spermidine. This action of spermidine, thought to be mediated by a membrane component other than phospholipase C, may reflect a control mechanism modulating the response of the polyphosphoinositide system.

Adult↗
PubMed1989

Glyceraldehyde phosphate: an insulin secretagogue with possible effects on inositol phosphate formation in pancreatic islets.

The insulinotropic action of glucose, the most potent physiologic insulin secretagogue, involves its metabolism. However, no glucose metabolite has ever been identified as a key intermediate. We tested the abilities of a number of glucose metabolites to stimulate insulin release from pancreatic islets. Of all of these metabolites, glyceraldehyde 3-phosphate was the most potent insulin secretagogue. In numerous experiments over 3 years, insulin release by 4 mM glyceraldehyde phosphate ranged from 50 to 200% of that initiated by 16.7 mM glucose--a near-maximal insulin stimulus. At concentrations of 1 and 4 mM, glyceraldehyde phosphate was even more potent than the known secretagogues glucose and glyceraldehyde. Glucose metabolites were also tested for their ability to stimulate inositol tris-, bis-, and monophosphate formation by permeabilized islets. Only glyceraldehyde phosphate stimulated inositol phosphate formation and this stimulation occurred at concentrations of glyceraldehyde phosphate which could be present in the beta cell under physiologic conditions (K0.5 = 25 microM). The current results are consistent with the idea that glyceraldehyde phosphate is a key insulinotropic glucose metabolite that might act directly (or rather directly via a receptor) on the phospholipase C that forms inositol trisphosphate in the plasma membrane.

Animals↗
PubMed1992

Memantine stimulates inositol phosphates production in neurones and nullifies N-methyl-D-aspartate-induced destruction of retinal neurones.

Whereas carbachol, noradrenaline, serotonin and memantine stimulated inositol phosphates production and calcium mobilization in 3-5 day old rabbit retinal cultures, only carbachol and noradrenaline were effective when 25-30 day old cultures were used. The older retinal cultures contain only Müller cells which shows that the memantine and serotonin effects on the 3-5 day old cultures are specifically associated with neurones. While the carbachol, noradrenaline and serotonin effects were respectively blocked by atropine, prazosin and ketanserin, none of these substances influenced the memantine responses. In all areas of the rat brain which were analysed, the effectiveness of memantine, noradrenaline and carbachol on the stimulation of inositol phosphates production was similar. However, in the rabbit retina, as opposed to the rat brain slices, carbachol had a more pronounced influence than noradrenaline in stimulating inositol phosphates production. Chick retina exposed to N-methyl-D-aspartate, quisqualate, glutamate or kainic acid resulted in cytopathological damage to cell bodies in the outer nuclear layer. The N-methyl-D-aspartate effect was nullified by memantine and MK-801 but not by kynurenic acid. In contrast the kainic acid-induced damage was specifically antagonized by kynurenic acid. The present results show that memantine influences the metabolism of inositol phosphates in neurones but not glial (Müller) cells and appears to counteract the N-methyl-D-aspartate induced cytopathological damage. How these two effects of memantine are interrelated and whether they are involved in the described beneficial therapeutic observations of memantine (as in dementia) remains to be established.

Animals↗
PubMed1989

Eicosapentaenoic acid interferes with U46619-stimulated formation of inositol phosphates in washed rabbit platelets.

Eicosapentaenoic acid (EPA) inhibits platelet responsiveness to aggregating agents. To investigate the reactions that are affected by EPA, we examined the effect of preincubating aspirin-treated rabbit platelets with EPA on stimulation of inositol phosphate formation in response to the TXA2 analogue U46619. Stimulation of platelets with U46619 (0.5 microM) caused aggregation and slight release of dense granule contents; aggregation and release were inhibited by preincubation of the platelets with EPA (50 microM) for 1 h followed by washing to remove unincorporated EPA. Incubation with EPA (50 microM) for 1 h did not cause a detectable increase in the amount of EPA in the platelet phospholipids. When platelets were prelabelled with [3H]inositol, stimulation with U46619 of control platelets that had not been incubated with EPA significantly increased the labelling of inositol phosphates. The increases in inositol phosphate labelling due to U46619 at 10 and 60 s were partially inhibited by preincubation of the platelets with 50 microM EPA. Since the activity of cyclo-oxygenase was blocked with aspirin, inhibition of inositol phosphate labelling in response to U46619 indicates either that there may be inhibition of signal transduction without a detectable change in the amount of EPA in platelet phospholipids, that changes in signal transduction require only minute changes in the fatty acid composition of membrane phospholipids, or that after a 1 h incubation with EPA, activation of phospholipase C is affected by a mechanism that is not directly related to incorporation of EPA.

Animals↗
PubMed1989

Effect of cholecystokinin on the accumulation of inositol phosphates in isolated pancreatic islets.

Sulfated cholecystokinin octapeptide (CCK-8S) potentiated glucose-induced secretion in isolated pancreatic islets with a maximal effect at 12 mM glucose, whereas no effect was observed at 3.3 and 25 mM glucose. This effect of CCK-8S was maximal at 10(-7) M. Anion-exchange fast-protein liquid chromatography analysis of [3H]inositol phosphates derived from islets prelabeled with myo-[3H]inositol showed that glucose induced accumulation of the 1,4,5-isomer of inositol trisphosphate and of inositol tetrakisphosphate. At 3.3 mM glucose, CCK-8S stimulated accumulation of inositol trisphosphate and inositol tetrakisphosphate to levels induced by 25 mM glucose alone. The net effect of CCK-8S on the accumulation of the inositol phosphates was maximal at 12 mM glucose and decreased at higher glucose concentrations. At 12 mM glucose the accumulation of inositol phosphates increased gradually up to 10(-7) M CCK-8S. This study indicates that CCK-8S potentiates glucose-induced insulin secretion through a mechanism involving the hydrolysis of polyphosphoinositides and the generation of inositol phosphates. However, activation of the inositol cycle per se did not seem to induce insulin secretion.

Animals↗
PubMed1989

Thrombin stimulates inositol phosphate accumulation and prostacyclin synthesis in human endothelial cells from umbilical vein but not from omentum.

We have compared the effects of thrombin on the accumulation of inositol phosphates and the synthesis of prostacyclin in cultured human endothelial cells from umbilical vein and the microvasculature of omentum. Active human thrombin induced a dose-dependent accumulation of inositol phosphates and a concomitant synthesis of prostacyclin in endothelial cells from human umbilical vein. However, thrombin at all concentrations tested was unable to stimulate inositol phosphate accumulation and prostacyclin synthesis in microvascular endothelial cells from human omentum. Bradykinin was able to stimulate these effects in both types of cell. These results demonstrate that although inositol phosphate turnover is an initial event associated with prostacyclin synthesis in endothelial cells, there are differences in the way microvascular endothelial cells respond to thrombin.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Aroclor 1242 stimulates the production of inositol phosphates in polymorphonuclear neutrophils.

Exposure in vitro to the mixture of polychlorinated biphenyls (PCBs), Aroclor 1242, stimulates superoxide anion (O2-) production and degranulation in rat polymorphonuclear neutrophils (PMNs). The mechanism by which PCBs activate PMNs is unknown. Phospholipase C-dependent hydrolysis of membrane phosphoinositides is an important early event in PMN activation in response to several agonists including N-formyl-methionyl-leucyl phenylalanine (fMLP); therefore, the present study was undertaken to determine whether Aroclor 1242 stimulates the production of inositol phosphates in isolated rat PMNs. PMNs elicited with glycogen from rat peritoneum were labeled with myo-[2-3H]inositol, and the effect of fMLP and Aroclor 1242 on accumulation of [3H]inositol phosphates was determined. Both fMLP (in the presence of cytochalasin B) and Aroclor 1242 induced rapid breakdown of inositol-containing phospholipids. Peak accumulation of [3H]inositol phosphates occurred within 5 sec in response to Aroclor 1242 and within 15-30 sec in response to fMLP. In cytochalasin B-treated PMNs, significant O2- generation occurred within 5 min of exposure to fMLP or Aroclor 1242. 2,2',4,4'-Tetrachlorobiphenyl (TCB), but not 3,3',4,4'-TCB, stimulates O2- production and degranulation in isolated rat PMNs. To determine whether inositol phosphate accumulation parallels PMN activation, [3H]inositol monophosphate (IP) production was measured in response to Aroclor 1242, 2,2'4,4'-TCB, and 3,3'4,4'-TCB in LiCl-treated cells. Both Aroclor 1242 and 2,2',4,4'-TCB, but not 3,3',4,4'-TCB, caused significant accumulation of [3H]IP. Previous reports indicate that cytochalasin B enhances PMN activation in response to fMLP by increasing the production of inositol phosphates. Pretreatment of PMNs with cytochalasin B significantly enhanced O2- production in cells exposed to Aroclor 1242 but did not alter [H]IP accumulation. These data suggest that treatment of rat PMNs with Aroclor 1242 stimulates PI turnover and are consistent with the hypothesis that hydrolysis of membrane phospholipids is important in PMN activation by PCBs. The enhancing effect of cytochalasin B on PCB-induced O2- production, however, likely involves other mechanisms.

Amino Acid Sequence↗
PubMed1990

Metabolism of the biologically active inositol phosphates Ins(1,4,5)P3 and Ins(1,3,4,5)P4 by ovarian follicles of Xenopus laevis.

The metabolism of biologically active inositol phosphates in developed ovarian follicles from Xenopus laevis was investigated. Techniques used were microinjection of tracer into the intact oocyte coupled by gap junctions to follicle cells, as well as addition of tracer to homogenates of ovarian follicles and to homogenates of oocytes stripped of outer follicle-cell layers. Metabolism was similar to that previously described for other types of cell and tissue, with several unusual features. Homogenates of ovarian follicles were shown to contain an apparent 3'-phosphomonoesterase capable of converting [3H]Ins(1,3,4,5)P4 predominantly into a substance with h.p.l.c. elution characteristics of Ins(1,4,5)P3. In intact ovarian follicles, little Ins(1,4,5)P3 was formed but the esterase was activated by the phorbol ester activator of protein kinase C, PMA (phorbol 12-myristate 13-acetate; 60 nM), as well as by acetylcholine (200 microM). In follicle homogenates, this enzyme also appeared to be active in converting [3H]Ins(1,3,4)P3 into a substance eluting as Ins(1,4)P2. The apparent 3'-phosphomonoesterase activity was not inhibited by intracellular (or higher) levels of Mg2+. Although PMA activated this enzyme in intact oocytes relative to 5'-phosphomonoesterase activation, it did not enhance overall metabolism, in contrast with reports on other tissues. Compared with the processing of inositol phosphates injected into the intact follicle, homogenization in simulated intracellular medium appeared to alter the activity and/or accessibility of several enzymes. The metabolism of inositol phosphates appears to occur predominantly in the follicle cells surrounding the oocyte, as collagenase treatment followed by defolliculation greatly diminished the rates of metabolism of several inositol phosphates. The presence in Xenopus ovarian follicles of a 3'-phosphomonoesterase activated by protein kinase C in addition to the well-known 3'-kinase suggests that, by forming a reversible interconversion between Ins(1,4,5)P3 and Ins(1,3,4,5)P4, this tissue may have the potential to prolong stimulatory signals on binding of appropriate agonists to receptors.

Acetylcholine↗
PubMed1987

Stimulation by bradykinin, angiotensin II, and carbachol of the accumulation of inositol phosphates in PC-12 pheochromocytoma cells: differential effects of lithium ions on inositol mono- and polyphosphates.

Rat PC-12 pheochromocytoma cells respond to stimulation with bradykinin, angiotensin II, and carbachol with an increased formation of labeled inositol phosphates after preincubation of the cells with [3H]inositol. Li+ potentiates greatly the agonist-induced increase in amount of inositol mono-, bis-, and trisphosphate but not the increase in amount of inositol tetrakisphosphate. Separation of the isomers of inositol trisphosphate shows that the lithium-induced increase in amount of inositol trisphosphate is due to potentiation evoked by lithium of the accumulation of inositol-1,3,4-trisphosphate.

Adrenal Gland Neoplasms↗
PubMed1986

Accumulations of inositol phosphates and cyclic AMP in brain slices: synergistic interactions of histamine and 2-chloroadenosine.

2-Chloroadenosine, 5'-N-ethylcarboxamidoadenosine, N6-cyclohexyladenosine and other adenosine analogs enhance histamine-elicited, but not norepinephrine- or carbamylcholine-elicited accumulations of inositol phosphates in [3H]inositol-labeled guinea-pig cerebral cortical slices. The adenosine analogs alone have no effect on accumulations of inositol phosphates. The effect of 2-chloroadenosine is blocked by the adenosine receptor antagonists theophylline and 1,3-dialkyl-8-p-sulfophenylxanthines. The rank order of activity of the six adenosine analogs with respect to augmentation of histamine-elicited accumulation of inositol phosphates in guinea-pig cerebral cortical slices is different from the rank order at an A2-adenosine receptor that mediates synergistic accumulations of cyclic AMP by adenosine analogs and histamine in guinea-pig cerebral cortical slices.

2-Chloroadenosine↗