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PubMed1990

Platelet activating factor induces inositol phosphate accumulation in cultures of rat and bovine anterior pituitary cells.

The phospholipid platelet-activating factor (PAF) (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) stimulated the accumulation of inositol phosphates in cultures of rat and bovine anterior pituitary cells. In response to PAF, inositol 1,4-bisphosphate showed the largest percent increase of the inositol phosphates in the presence of lithium chloride. PAF induced an increase of inositol 1,4,5-trisphosphate, the biologically active isomer responsible for mobilization of intracellular calcium. A characterization of the PAF response indicated that PAF, but not its biologically inactive enantiomer, induced the accumulation of inositol phosphates in the rat anterior pituitary. Further, the PAF receptor antagonist L652731 reduced PAF stimulation. The ED50 for PAF-induced inositol 1,4-bisphosphate accumulation was 0.4 nM. PAF induced a rapid response that did not persist beyond 20 min. While PAF treatment of anterior pituitary cells did not alter TRH-induced inositol phosphate accumulation, it did prevent a second exposure of PAF from inducing inositol phosphate accumulation. These data suggest that PAF induces a rapid stimulation of phospholipase C causing the hydrolysis of phosphatidylinositol 4,5-bisphosphate and the generation of the second messengers, inositol 1,4,5-trisphosphate and diglyceride, in anterior pituitary tissue. This action is transient probably due to PAF receptor desensitization. The action of PAF on generation of inositol phosphates may account, in part, for PAF-induced secretion of PRL and GH.

Animals↗
PubMed1991

Inositol cycling and phosphoinositide metabolism in rat pancreatic islets.

The effects of extracellular inositol and LiCl on intra-islet inositol cycling were investigated in isolated rat islets. Islets were cultured for 7 days in inositol-free RPMI 1640 containing 11.1 mM glucose and labeled with 3.7 MBq myo-[2-3H] inositol for the final 3 days. The labeled islets were then perifused under various conditions. There was a persistent increase in [3H] efflux from labeled islets stimulated with 16.7 mM glucose for 60 min. Addition of 5 mM inositol resulted in marked release of [3H] from islets and a decrease in radioactive inositol-lipid. When islets were perifused with 5 mM LiCl, the glucose-induced efflux of [3H] was greatly inhibited. The inhibitory effect of LiCl on [3H] efflux was partially corrected by the addition of 5 mM inositol. A prominent effect of LiCl was an increase in inositol monophosphate, indicating increased phospholipase C activity. This was detected within 5 min after glucose stimulation. The present data suggest that there is always very active intra-islet inositol cycling and that glucose can augument inositol-lipid metabolism.

Animals↗
PubMed1989

The Albert Lasker Medical Awards. Inositol trisphosphate, calcium, lithium, and cell signaling.

Inositol lipids play a major role in cell signaling by functioning as precursors of second messengers. Of the three common inositol-containing lipids found in the plasma membrane, phosphatidylinositol (4,5)-bisphosphate is hydrolyzed to give diacylglycerol, which stimulates protein kinase C, and inositol 1,4,5-trisphosphate, which diffuses into the cell to release intracellular calcium. Inositol 1,4,5-trisphosphate is metabolized to give free inositol by two separate pathways. Lithium inhibits the final dephosphorylation step of both pathways, thus reducing the supply of the free inositol required to maintain the lipid precursors used for signaling. An inositol-depletion hypothesis may explain both the teratogenic effects of lithium and its therapeutic action in controlling manic-depressive illness. One of the metabolic pathways generates inositol tetrakisphosphate, which may also play a messenger role by expanding the size of the inositol 1,4,5-trisphosphate-sensitive pool of calcium. Calcium imaging of single cells has begun to reveal that this inositol 1,4,5-trisphosphate/calcium signaling system is organized in complex patterns, which include localization of calcium signals to discrete regions of cells and the generation of both calcium waves and calcium oscillations.

Animals↗
PubMed1996

Effect of pertussis toxin and B-oligomer on platelet-activating factor-induced generation of inositol phosphates in porcine alveolar macrophages.

OBJECTIVE: To test the hypothesis that platelet-activating factor (PAF) induces inositol phosphate turnover through a receptor-linked, pertussis toxin-sensitive guanine nucleotide-binding (G) protein-dependent pathway in porcine alveolar macrophages. DESIGN: Randomized complete block design was used with 2 or 3 replicates/block. ANIMALS: Porcine alveolar macrophages were obtained by lavage of excised lungs from Yorkshire-type pigs (mean +/- SEM, 21 +/- 2 kg). PROCEDURE: Phospholipase C activation was assessed, using anion exchange chromatography to measure accumulation of inositol phosphates in [3H]myo-inositol-labeled alveolar macrophages. Macrophages were incubated with saline solution, pertussis toxin (4.75 nM), or B-oligomer (4.75 nM) for 2 hours. Cells then were washed and incubated for 5 minutes with PAF (0, 0.1, 1.0, or 10 microM; n = 15). Results were expressed as total inositol phosphates (inositol monophosphate, bisphosphate, trisphosphate, and tetrakisphosphate). RESULTS: Concentrations of total inositol phosphates were significantly (P < 0.05) increased to 162 +/- 7, 172 +/- 4, and 194 +/- 9% of control in response to 0.1, 1.0, and 10 microM PAF, respectively. Pertussis toxin attenuated the PAF-induced increase in total inositol phosphates by approximately 50% (P < 0.05). The B-oligomer of pertussis toxin failed to modify PAF-induced increases in total inositol phosphates. The specific PAF receptor antagonist WEB 2086 markedly attenuated PAF-induced. (10 microM) increase in inositol phosphates. CONCLUSIONS: We conclude that PAF stimulates accumulation of inositol phosphates through a specific receptor and that a pertussis toxin-sensitive G protein is involved in the signal transduction process leading to activation of phospholipase C in porcine alveolar macrophages.

Adenosine Diphosphate Ribose↗
PubMed1994

Osmoregulatory changes in myo-inositol content and Na+/myo-inositol cotransport in rat cortical astrocytes.

Exposure of cortical astrocytes to 325, 350, or 390 mosM culture media for 48 h caused a 1.4-, 2.1-, and 3.5-fold increase, respectively, in cellular content of the compatible osmolyte myo-inositol. Elevated myo-inositol levels accounted for approximately 56-100% of the solute needed by the cells for complete volume regulation under hypertonic conditions. Myo-inositol accumulation was associated with 4-5-fold (peak rate) and 1.8-2-fold (steady-state rate) increases in the rate of Na(+)-dependent myo-inositol uptake when cells were acclimated to 390 mosM culture medium for 12 h or 24-96 h, respectively. When medium osmolality was elevated by 25 mosM, peak and steady-state increases in myo-inositol uptake of 1.7-fold and 1.3-fold, respectively, were observed. Exposure to 390 mosM medium for 12-48 h induced a 3-8-fold increase in cotransporter mRNA levels suggesting that the increase in myo-inositol uptake is brought about by increased cotransporter gene expression. Abrupt return of hypertonic cells to an isotonic medium induced a rapid increase in myo-inositol efflux and a return of cotransporter mRNA to control values in < 2 h. In contrast, the cotransporter remained fully activated at hypertonic levels for 16 h. Between 16-24 h after the transfer, the rate of myo-inositol uptake returned to control values. The remarkable sensitivity of the cotransporter to hypertonic stress indicates that upregulation of myo-inositol transport in glial cells is likely to occur in a variety of disease states that cause an elevation of plasma osmolality. Slow downregulation of the cotransporter may be responsible in part for the slow loss of myo-inositol and cerebral edema that occurs with too rapid correction of chronic plasma hypertonicity.

Animals↗
PubMed1990

Differences in inositol phosphate production in rat tail artery and thoracic aorta.

Pharmacomechanical coupling of vascular smooth muscle is believed to be mediated by inositol trisphosphate (IP3). Numerous studies have demonstrated an increase in inositol phosphates following tissue stimulation using either intact aortic strips or cultured cells from aorta. However, little information is available concerning inositol phosphates in vascular tissue other than in the large conduit vessel, the aorta. This present study was designed to examine the role of inositol phosphate metabolism following adrenergic stimulation of the muscular rat tail artery as compared to the aorta. Segments of thoracic aorta and tail artery from male Sprague Dawley rats were labeled with [3H]inositol and stimulated with norepinephrine. The norepinephrine concentration that resulted in a half-maximal stimulation of inositol phosphates was approximately 10(-6) M in both the aorta and tail artery. Although the sensitivity of the two vessels to norepinephrine stimulation were similar, the stimulated levels of IP, IP2, and IP3 were from 1 to 2 orders of magnitude greater in the tail artery than in aorta. IP production in aorta and tail artery was a linear function of time (from 0 to 30 min). Significant levels of IP3 (the 1,4,5-IP3 isomer as determined by HPLC) could only be detected in the tail artery and appeared to be produced optimally after 5 min of stimulation. The several order of magnitude increase in adrenergic stimulated inositol phosphate production in the tail artery was not due to either an increased magnitude of [3H]inositol incorporated into PI, PIP, and PIP2 or to a greater percentage of smooth muscle cells per unit tissue of the rat tail artery. We believe the results of this study demonstrate that the increased inositol phosphate metabolism in the vascular smooth muscle cells of the tail artery is an intrinsic property of the cell. Moreover, due to the significant levels of all inositol phosphates produced in the tail artery, this muscular artery may be a better model, as compared to the aorta, for future studies investigating pharmacomechanical coupling of vascular smooth muscle.

Animals↗
PubMed1993

The isolation of adult rat cardiomyocytes activates inositol(1,4,5) trisphosphate 3'kinase activity.

Addition of norepinephrine to [3H]inositol-labeled rat hearts or isolated left atria caused the release of inositol(1,4,5)trisphosphate which was metabolized by dephosphorylation to inositol(4)monophosphate. Products of the inositol(1,4,5)trisphosphate 3'-kinase pathway were not present at detectable levels. When norepinephrine was added to [3H]inositol-labeled isolated adult cardiomyocytes the released inositol(1,4,5)trisphosphate was metabolized partially by phosphorylation as evidenced by the presence of the immediate phosphorylation product inositol(1,3,4,5)-tetrakis-phosphate and its dephosphorylation products inositol (1,3,4)trisphosphate and inositol(1,3)-bisphosphate. Direct measurement of inositol trisphosphate 3'-kinase activity in cytosols prepared from intact hearts and isolated myocytes demonstrated activation of the enzyme during cell isolation from 20 +/- 0.5 p mol/min/mg protein to 124 +/- 14 (mean +/- S.E.M., n = 3, P < 0.001). These data show that the kinase pathway is suppressed in healthy heart tissue and show that it can be activated under conditions such as those required for cell isolation.

Animals↗
PubMed1978

Inositol deficiency in yeast: metabolic, enzymatic and autoradiographic studies.

The addition of inositol to starved cells of Saccharomyces cerevisiae NCYC 86 resulted in an initiation of growth. Inositol was incorporated into phosphatidyl-inositol and after a lag period RNA was the first macromolecule with a rate of synthesis departing from the rate observed in deprived cells. Pulse chase experiments showed that inositol was first incorporated into phosphatidylinositol and later into more polar lipids. Finally it appeared to be excreted into the surrounding medium. When S. cerevisiae NCYC 86 was grown in suboptimal concentrations of inositol (0,5 microgram/ml), alterations in the level of some membrane-bound enzymatic activities were detected; these might reflect structural modifications of the cellular membranes due to a different composition of phospholipids. High-resolution autoradiography showed that inositol was probably first incorporated into internal membranes and later transferred to the plasma membrane. Analytical experiments carried out with inositol-deprived cells showed that inositol was released into the surrounding medium in that case. The unbalanced growth detected in S. cerevisiae NCYC 86 under inositol deprivation might be due to an abnormal functioning of the cell membranes as a consequence of the deficiency in inositol-containing phospholipids.

Autoradiography↗
PubMed2000

The anxiolytic effect of chronic inositol depends on the baseline level of anxiety.

Inositol, a precursor for membrane phosphoinositides involved in signal transduction, has been found to be clinically effective in a number of psychiatric disorders and to reverse behavioural effects of lithium. To gain insight into the mechanism of action of inositol, it is critical to establish its efficacy in animal models. Following the initial report by Cohen et al. (1997b) that inositol was anxiolytic in the elevated plus maze model of anxiety, the effect of chronic intraperitoneal and chronic dietary inositol administration in rats was tested in four experiments. There was a significant increase in closed arm and total arm entries following chronic injection of inositol, but no effect of inositol when it was given chronically in rat chow. Because the first 2 experiments suggested that the mode of drug administration affected the control levels of anxiety (open arm entries and time in open arms) in control groups, the effect of chronic dietary inositol was tested in rats that were exposed to a mild and a more severe form of stress. Chronic saline injections elevated anxiety in the plus maze, which was only marginally affected by chronic dietary inositol. Following 3 weeks administration of 5% dietary inositol rats were pre-exposed to a cat. There was a clear increase in number of entries into open arms, suggesting an anxiolytic effect of inositol.

Animals↗
PubMed1991

Regulation of phosphatidylserine decarboxylase in Saccharomyces cerevisiae by inositol and choline: kinetics of repression and derepression.

The biosynthesis of phosphatidylserine (PS) and its conversion to phosphatidylcholine (PC) are regulated coordinately by inositol and choline in Saccharomyces cerevisiae (G. M. Carman and S. A. Henry, 1989, Annu. Rev. Biochem. 58, 635-669). In this study, PS decarboxylase activity is shown to be partially repressed when inositol is added to the medium of cells in the log phase of growth, and the extent of repression is augmented by the inclusion of choline, but not ethanolamine. The kinetics of repression and derepression of PS decarboxylase, PS synthase, and phospholipid N-methyltransferase (PNMT) activities, as regulatory responses to the availability of exogenous inositol and choline, have been characterized. When inositol was added to the medium of cell cultures growing exponentially, the three biosynthetic enzyme activities reached an intermediate level of repression (50-85% of control) within 60 min. After the addition of the combination of inositol and choline, PS decarboxylase, PS synthase, and PNMT activities decreased to the intermediate levels of repression in 60 min and were subsequently reduced to 15-40% of control values during a later stage of regulation (2-3 h). In a derepression study, the three enzyme activities remained relatively stable for approximately 60 min following the removal of choline and/or inositol from the growth medium, but the specific activities of PS decarboxylase, PS synthase, and PNMT increased to maximally derepressed levels within 2-3 h. The induction of the three biosynthetic activities was blocked by cycloheximide, but not by chloramphenicol. In summary, the level of PS decarboxylase activity in S. cerevisiae is partially and reversibly suppressed by inositol and further diminished by the combination of inositol and choline. The biphasic kinetics of repression by inositol and choline suggest that the effect of choline is dependent on earlier events mediated by inositol and possibly involves a separate regulatory factor(s).

Allosteric Regulation↗
PubMed1985

The 5-hydroxyl of myo-inositol is essential for uptake into HSDM1C1 mouse fibrosarcoma cells.

We attempted to replace the myo-inositol in cellular inositol phosphatides with 5-deoxy-myo-inositol to evaluate the role of inositol 1,4,5-trisphosphate as a second messenger. This analog, lacking a 5-hydroxyl, might be incorporated into 5-deoxyphosphatidylinositol and converted to the corresponding phosphatidylcyclitol 4-phosphate but could not be converted to phosphatidylinositol 4,5-diphosphate, the precursor of the second messenger molecule inositol 1,4,5-trisphosphate. We synthesized 5-deoxy-myo-inositol and found that this analog does not replace myo-inositol as an essential growth factor for essential fatty acid deficient HSDM1C1 mouse fibrosarcoma cells. Furthermore, [5-3H]-5-deoxy-myo-inositol was neither incorporated into the phospholipids nor accumulated in the cytoplasm of these cells. It appears that this cell line has a specific myo-inositol uptake system that excludes a potentially harmful analog of inositol.

Animals↗
PubMed1992

Light stimulates in vivo inositol lipid turnover in frog retinal pigment epithelial cells at the onset of shedding and phagocytosis of photoreceptor membranes.

We have developed an experimental model to study in vivo inositol lipid metabolism in frog retinal pigment epithelial (RPE) cells, including the effect of light on phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate. RPE cells were rapidly isolated after either brief light or dark periods. Light and electron microscopy showed complete detachment of the retina from the RPE cells, and that the RPE cell suspensions were devoid of photoreceptor cell outer segments. Frog tissues were labeled in vivo for 20 hr by intravitreal injection of [3H]inositol (4 microCi, 4 microliters per eye) within a 24-hr constant illumination period. Following 1 hr of darkness (priming period), frogs were intravitreally injected with LiCl (0.5 M, 4 microliters per eye) 15 min before the onset of either 30-min light stimulation or an additional 30 min of darkness (controls). In order to preserve endogenous inositol phosphate pools present after dark and light exposure, the RPE cells were harvested in the shortest time possible, at low temperatures (18-20 degrees C), and in the presence of 10 mM LiCl. Total [3H]inositol-labeled water-soluble products (inositol plus inositol phosphates) were increased by 86% after 30 min of light. Inositol trisphosphate (IP3) showed the highest accumulation (a 5.5-fold increase), followed by inositol bisphosphate (1.9-fold increase) and inositol monophosphate (1.4-fold increase). Free [3H]inositol also accumulated (2.8-fold increase), reflecting only a partial inhibition of phosphomonoesterase by LiCl. These changes were paralleled by a 12% decrease in 3H-labeled phosphatidylinositol with no significant difference in the labeling of polyphosphoinositides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Scyllo-inositol depletion in hepatic encephalopathy.

Cerebral myo-inositol depletion is found in patients with hepatic encephalopathy and can be implicated in the pathogenesis of hepatic encephalopathy. We measured scyllo-inositol, a stereoisomer of myo-inositol, in brain extracts from patients dying in hepatic coma using HPLC and high resolution 1H MRS. The cerebral scyllo-inositol concentration, determined by both methods, in patients without hepatic encephalopathy was 0.41 +/- 0.11 mmol/kg wet weight. It decreased by 73% and 76%, respectively, as measured by HPLC and 1H MRS, in patients with hepatic encephalopathy. These findings indicate that myo-inositol depletion in patients with hepatic encephalopathy is not due to enhanced conversion of myo-inositol to scyllo-inositol or inhibition of myo-inositol transport by scyllo-inositol, but rather to the reduced biosynthesis or transport of both inositols.

Autopsy↗
PubMed1990

Interactions between cyclic AMP and inositol phosphate transduction systems in astrocytes in primary culture.

Astroglial cells in primary culture possess receptors with cyclic AMP and inositol phosphates (IP) as second messengers. The beta-receptor agonist, isoproterenol induces an increase in the accumulation of cyclic AMP, the alpha 2-receptor agonist clonidine inhibits the isoproterenol-induced accumulation of cyclic AMP, while the alpha 1-receptor agonist phenylephrine acts only on the inositol phosphate system. 5-Hydroxytryptamine (5-HT) stimulates, the formation of inositol phosphate, while isoproterenol and clonidine per se do not affect the inositol phosphate system. In the present paper the possibility of interactions between the cyclic AMP and the inositol phosphate transduction systems were investigated. In the presence of 10(-5) M 5-HT, in itself ineffective on the formation of cyclic AMP, isoproterenol stimulated the accumulation of cyclic AMP far more than in the absence of 5-HT. The potentiation was blocked by the 5-HT2 receptor antagonist ketanserin. On the other hand, there were no indications for a beta-receptor influence on the 5-HT-induced inositol phosphate formation. Stimulation of the alpha 2-receptor did not induce accumulation of inositol phosphate but significantly potentiated 5-HT2-receptor transduction, as measured by hydrolysis of phosphoinositide and formation of inositol phosphate. Stimulation by 5-HT also increased the formation of inositol phosphate after adrenergic stimulation and this effect was found to be synergistic at certain concentrations of adrenergic agonists. In addition, there was a statistically significant accumulation of cyclic AMP in the presence of both 5-HT and phenylephrine, none of which stimulated cyclic AMP alone. The results suggest specific interactions between the cyclic AMP and inositol phosphate systems on cultured astroglial cells.

Adenylyl Cyclases↗
PubMed1983

Possible role of a regulatory gene product upon the myo-inositol-1-phosphate synthase production in Neurospora crassa.

The regulatory effect of inositol on inositol-1-phosphate synthase in Neurospora crassa strains was studied. Inositol represses enzyme production in the cultures of the wild type and that of the thermosensitive inositol-requiring mutant grown at 22 degrees C. Enzyme activity as well as the quantity of enzyme protein decreased sharply in both strains by increasing concentrations of inositol in the medium. Inositol-requiring strains used in our experiments can be divided into two groups. The first group produces a protein related immunologically to inositol phosphate synthase, but which is enzymatically inactive. The synthesis of this defective enzyme was also repressed by inositol. In the second group, this protein was found to be completely lacking, in both the thermosensitive mutant grown at 37 degrees C, and in a strain requiring inositol due to a reciprocal translocation. The thermostability and the cross immunoelectrophoresis of the enzyme suggest that in the case of the thermosensitive inositol-requiring mutant, the mutation did not occur in the structural gene of the enzyme, but its regulation was probably affected.

Carbohydrate Epimerases↗
PubMed1989

Carbamoylcholine-induced accumulation of inositol mono-, bis-, tris- and tetrakisphosphates in isolated cardiac myocytes from adult rats.

The effect of carbamoylcholine on the phosphoinositide cycle in isolated ventricular myocytes from adult rats was studied. Separation of the phosphoinositides by high-performance thin-layer chromatography showed a constant ratio of incorporation of myo-[2-3H]inositol into phosphatidylinositol, phosphatidylinositol 4-monophosphate and phosphatidylinositol 4,5-bisphosphate of cultured cardiac myocytes after at least 2 h. Carbamoylcholine caused a dose-dependent and time-dependent accumulation of inositol mono-, bis- and trisphosphates, which was antagonized by atropine. Using anion-exchange HPLC the existence of inositol 1,4,5-trisphosphate, inositol 1,3,4-triphosphate and inositol 1,3,4,5-tetrakisphosphate was confirmed in rat ventricular myocytes. Inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate accumulated within 20 s, while inositol 1,3,4-trisphosphate, inositol 1,4-bisphosphate and inositol monophosphate increased within 5 min.

Animals↗
PubMed1994

Sulphur-containing excitatory amino acid-stimulated inositol phosphate formation in primary cultures of cerebellar granule cells is mediated predominantly by N-methyl-D-aspartate receptors.

The stimulatory effect of excitatory sulphur-containing amino acids on inositol phosphate formation was investigated in primary cultures of cerebellar granule cells. L-Cysteine sulphinate (CSA), L-cysteate (CA), L-homocysteine sulphinate (HCSA), L-homocysteate (HCA) and S-sulpho-L-cysteine (SSC) dose-dependently stimulated the formation of [3H]inositol phosphates exhibiting EC50 values in the range 60-200 microM and maximal effects of six- to 17-fold that of basal [3H]inositol phosphate levels. Endogenous L-glutamate spontaneously released into the extracellular medium or following exposure of cells to HCSA, HCA or SSC did not contribute significantly to formation of [3H]inositol phosphates, whereas 10% of the total [3H]inositol phosphates accumulated following exposure to CSA and CA was due to released L-glutamate. The selective N-methyl-D-aspartate receptor antagonist, D,L-2-amino-5-phosphonopentanoic acid (APV, 500 microM) attenuated by 20% (HCSA) to between 80 and 100% (CSA, CA, SSC, HCA) the formation of [3H]inositol phosphates induced by 1 mM sulphur-containing amino acids. When, however, HCSA was used at 100 microM (a concentration near to its EC50 for phosphoinositide hydrolysis), APV inhibited induced responses by 70%. Sulphur-containing amino acid-stimulated [3H]inositol phosphate formation was unaffected by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). Inhibition of sulphur-containing amino acid-stimulated [3H]inositol phosphate formation by co-administration of APV and CNQX was similar to that obtained in the presence of APV alone. CSA-, CA-, SSC- and HCA-stimulated [3H]inositol phosphate formation was markedly reduced by removal of Ca2+ from the extracellular medium whereas that stimulated by HCSA was less affected. A similar inhibitory profile was observed when the levels of sulphur-containing amino acid-induced increases in intracellular free calcium ([Ca2+]i) were measured in the presence of 500 microM APV; 1 mM HCSA-induced responses being inhibited by only 30% whereas responses to the remaining sulphur-containing amino acid (also at 1 mM) were inhibited by > 45%. When the sulphur-containing amino acids were used at concentrations approximating their EC50 values for phosphoinositide hydrolysis, APV inhibited the induced increases in [Ca2+]i by 70-100%. HCA and SSC co-administered with the less efficacious but selective metabotropic glutamate receptor agonist, (+-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) at maximally effective concentrations (1 mM) of each agonist stimulated [3H]inositol phosphate formation in an additive manner.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Conformational studies of myo-inositol phosphates.

The discovery of the second messenger role of myo-inositol 1,4,5-trisdihydrogenphosphate [Ins(1,4,5)P3] has triggered tremendous interest in investigating the structure, metabolism, and biological roles of inositol phosphates. Although the conformation of phytic acid [(myo-inositol hexakisdihydrogenphosphate), Ins P6] has been the subject of much study, the conformations of lower inositol phosphates such as inositol-pentakis-, tetrakis-, and tris-dihydrogenphosphates have not been investigated. We investigated, by 1H NMR spectroscopy, the conformations of inositol phosphates (Ins P5, Ins P4, Ins P3, Ins P2, and Ins P1) and monitored the influence of pH on conformational preferences. Ins P6 adopts the sterically stable 1ax/5eq (one phosphate in the axial position and five phosphates in the equatorial position) conformation in the pH range 0.5-9.0, and the sterically hindered 5ax/1eq (five phosphates in the axial position and one phosphate in the equatorial position) conformation above pH 9.5. At pH 9.5, both conformations are in dynamic equilibrium. Ins(1,2,3,4,6)P5 and Ins(1,2,3,5,6)P5 adopt the 1ax/5eq form in the pH range 1.0-9.0; in the pH range 9.5-13.0, the 1ax/5eq and 5ax/1eq conformations are in dynamic equilibrium. In contrast to Ins P6 and Ins P5, all the lower inositol phosphates (Ins P4 to Ins P1) investigated adopt the 1ax/5eq conformation over the entire pH range, 1.0-13.0. Preference for the 5ax/1eq conformation by Ins P6 and Ins P5 is probably due to decreased electrostatic repulsion between negatively charged vicinal equatorial phosphates in the 1ax/5eq conformation and stabilization of the sterically hindered 5ax/1eq conformation by hydrogen bonding and/or sodium counter-ions bonding between the syn-oriented phosphates. On the basis of conformations adopted by the inositol phosphates (Ins P6 to Ins P1) at different pH, we conclude that the presence of four or five equatorial phosphates on the inositol ring induces a change in the conformation from the sterically unhindered 1ax/5eq structure to the sterically hindered 5ax/1eq conformation, at high pH. This investigation illustrates that the conformational preferences of inositol phosphates at different pH is unique to the particular isomer and does not parallel the behaviour of phytic acid.

6-Phytase↗