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PubMed1992

Analysis of [3H]inositol phosphate formation and metabolism in cerebral-cortical slices. Evidence for a dual metabolism of inositol 1,4-bisphosphate.

Muscarinic-receptor-mediated phosphoinositide hydrolysis in rat cerebral cortex was investigated by analysis of the kinetics of [3H]inositol phosphate formation and degradation in myo-[2-3H]inositol-labelled tissue slices. Carbachol stimulated rapid (5 s) increases in the concentrations of [3H]Ins(1,4,5)P3, [3H]Ins(1,3,4,5)P4 and [3H]Ins(1,4)P2. Stimulated accumulation of [3H]Ins(1,3,4)P3, [3H]Ins(1,3)P2 and [3H]Ins(3,4)P2 and [3H]Ins(1/3)P or of [3H]Ins(4)P occurred only subsequently and with a sequence indicating formation by successive dephosphorylation of [3H]Ins(1,3,4,5)P4 or of Ins(1,4)P2 respectively. A similar sequence was inferred from the order of rapidity with which the accumulations of [3H]inositol polyphosphates, resulting from sustained (5 min) carbachol stimulation in the presence of LiCl, were reversed when muscarinic receptors were subsequently blocked with atropine. During this latter period of receptor blockade, radiolabel lost from [3H]inositol polyphosphates was quantitively recovered as [3H]inositol monophosphates owing to effective inhibition of monophosphatase by Li+, and the rate of poly- into mono-phosphate conversion was similar to agonist-stimulated rates of monophosphate accumulation. This implies that, even during persistent stimulation, polyphosphoinositide, not PtdIns, is the substrate for phosphoinositidase C. Quantitative comparison of the degradation of [3H]inositol poly- to mono-phosphates after receptor blockade unexpectedly suggests the dual hydrolysis of [3H]Ins(1,4)P2 to [3H]Ins(1)P and [3H]Ins(4)P. This result advises cautious interpretation of the origin of [3H]Ins(1)P in stimulated tissue, but, with other data presented, allows calculation from the observed ratio of [3H]Ins(1/3)P:[3H]Ins(4)P that a minimum of approx. 50% of the [3H]Ins(1,4,5)P3 produced during persistent muscarinic-receptor stimulation is metabolized by Ins(1,4,5)P3 3-kinase.

Animals↗
PubMed1993

Turnover of inositol pentakisphosphates, inositol hexakisphosphate and diphosphoinositol polyphosphates in primary cultured hepatocytes.

We have used a non-transformed cell model, the primary cultured hepatocyte, to explore the turnover of inositol hexakisphosphate, multiple isomers of inositol pentakisphosphate and two novel diphosphoinositol polyphosphates. All of these compounds gradually accumulated radioactivity throughout a 70 h period of labelling with [3H]inositol. However, a rapid metabolic rate was revealed upon inhibition of diphosphoinositol polyphosphate biphosphatase(s) with 1 mM fluoride for 40 min: this treatment elevated levels of [3H]diphosphoinositol polyphosphates up to 10-fold, indicating that their cellular pools were normally turning over at least 10 times every 40 min. This was accompanied by a turnover of about 10% of the pool of inositol hexakisphosphate. Control experiments established that 200 nM vasopressin brought about a typical activation of phospholipase C in hepatocytes after 62 h of primary culture. This agonist treatment did not affect steady-state levels of [3H]inositol pentakisphosphates, [3H]inositol hexakisphosphate or [3H]diphosphoinositol polyphosphates. However, prolonged treatment of hepatocytes with 2 microM thapsigargin reduced steady-state levels of [3H]diphosphoinositol polyphosphates by 50-70%. This effect of thapsigargin was also observed in the presence of fluoride, indicating that thapsigargin inhibited the rate of synthesis of diphosphoinositol polyphosphates.

Cells, Cultured↗
PubMed1991

Cerebral lithium, inositol and inositol monophosphates.

Cerebral regional inositol, inositol-1-phosphate (Ins1P), and inositol-4-phosphate (Ins4P), intermediates in phosphoinositide (PI) cycle, and brain lithium levels were studied in male Han:Wistar rats 24 hr after an intraperitoneal injection of a single dose (2.5-18 mEq./kg) of LiCl. A dose of LiCl higher than 5 mEq/kg caused a remarkable accumulation of Li+ in the brain. Basal brain regional inositol levels (17-22 mmol/kg) were reduced by 6-8 mmol/kg dry brain tissue at doses exceeding 5 mEq/kg of LiCl in all brain regions except the piriform cortex. However, higher doses of LiCl did not cause any further decrease in brain inositol. LiCl increased basal brain regional Ins1P levels (170-240 mumol/kg) by 0.8 mmol/kg dry brain tissue at most, and there were no consistent additional increases of Ins1P at LiCl doses exceeding 5 mEq./kg. Moreover, lithium slightly decreased regional cerebral concentrations of Ins4P. Thus, lithium-induced accumulation of Ins1P or changes of Ins4P levels do not explain lithium-induced decrease in cerebral inositol. Effects of lithium on brain P1 turnover are likely to be multifocal and to differ markedly at different concentrations of Li+ in the brain.

Animals↗
PubMed1988

Influence of cAMP and calcium on [3H]inositol efflux, inositol phosphate accumulation, and insulin release from isolated rat islets.

The influence of cyclic AMP (cAMP) and extracellular calcium on phosphoinositide (PI) hydrolysis in isolated islets was assessed and related to insulin output. Three stimulants were chosen to activate the beta-cell: sulfated cholecystokinin (CCK-8S, 200 nM), high-level glucose (20 mM), and the sulfonylurea tolbutamide (200 microM). The insulin secretory response to all three agonists was amplified by forskolin (which increases cAMP levels) and reduced by nitrendipine (which decreases calcium influx). All three stimulants increased the hydrolysis of inositol-containing phospholipids, an event monitored by an increase in [3H]inositol efflux from [3H]inositol-prelabeled islets and by the accumulation of labeled inositol phosphates. Forskolin, despite its positive impact on insulin secretion, reduced [3H]inositol efflux and inositol phosphate accumulation in response to all agonists. A similar inhibitory effect on these parameters was noted with nitrendipine; however, nitrendipine abolished secretion in response to all agonists. These findings support the following conclusions: 1) an increase in cellular cAMP levels reduces the quantitative impact of various agonists on these indices of PI hydrolysis; 2) despite this inhibitory effect, cAMP amplifies the insulin secretory response to these agonists; and 3) extracellular calcium is a crucial determinant of both PI hydrolysis and the ensuing insulin secretory response.

Animals↗
PubMed1990

Sorbinil prevents the hypergalactosemic-induced reduction in [3H]-myo-inositol uptake and decreased [3H]-myo-inositol incorporation into the phosphoinositide cycle in bovine lens epithelial cells in vitro.

The synthesis of phosphatidylinositol, phosphatidylinositol-4-phosphate and phosphatidylinositol-4-5-bisphosphate was studied using 3H-myo-inositol (3H-MI) as precursor in cultured bovine lens epithelial cells (BLECs) maintained in galactose-free, physiological medium or 40 mM galactose (Gal) +/- sorbinil for six days. The formation of inositol polyphosphates from phosphoinositides was also shown. Galactitol did not exceed 2mM in Gal-incubated cells after six days of exposure; no galactitol was observed in BLECs maintained in galactose-free, physiological medium or Gal supplemented with sorbinil. Uptake of 3H-myo-inositol(3H-MI) into BLECs was significantly reduced in cells exposed to Gal. A concomitant reduction in 3H-MI incorporation was observed in the phosphoinositides, as well as with the released inositol phosphates. The simultaneous addition of sorbinil to the Gal medium corrected the drop in 3H-MI uptake and normalized 3H-MI incorporation into the phosphoinositides and inositol phosphates. While an apparent decrease in the three inositol-containing lipids was observed with the Gal-incubated cells, based on 3H-MI incorporation, there was no change in total membrane phosphatidylinositol content when compared to cells maintained in physiological medium as determined by the microgram Pl PO4 per microgram total membrane PO4. The apparent loss of radiolabeled phosphoinositides was attributed to the decreased specific activity resulting from the lower internal pool of 3H-MI in the Gal-exposed cells available for incorporation into the phosphoinositides.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗
PubMedDate not supplied

Dietary administration of inositol and/or inositol-6-phosphate prevents chemically-induced rat hepatocarcinogenesis.

Chemoprevention is considered a rational strategy for dietary approaches to prevention of cancer. Multiple lines of evidence suggest that many of our dietary principles are able to intervene in the multistage carcinogenesis process and phytic acid (inositol hexaphosphate, IP6), a phytochemical present in a variety of plant species, has been shown to prevent various cancers, including those of the mammary gland, colon and liver. However, the mechanism of chemoprevention by IP6 has not been fully elucidated. In the present study, we examined the effects of inositol and/or IP6 supplementation on rat hepatocarcinogenesis initiated by diethylnitrosamine (DEN) and promoted by partial hepatectomy (PH). Supplementation with either inositol or IP6, or their combination, starting one week prior to administration of DEN, resulted in a significant decrease in both the area and the number of placental glutathione S-transferase positive (GST-P+) foci, a preneoplastic marker for DEN-initiated hepatocarcinogenesis. The administration of inositol and/or IP6 in drinking water caused marked enhancement in the glutathione S-transferase (GST) activity. In addition, the production of thiobarbituric acid reactive substances and the catalase activity were significantly reduced in rats supplemented with inositol and /or IP6. Based on these findings, it is likely that the chemopreventive effects of inositol and/or IP6 on rat hepatocarcinogenesis initiated by DEN and promoted by PH are associated with induction of GST activity and suppression of lipid peroxidation.

Administration, Oral↗
PubMed1988

Kinetics of inositol 1,4,5-trisphosphate and inositol cyclic 1:2,4,5-trisphosphate metabolism in intact rat parotid acinar cells. Relationship to calcium signalling.

Stimulation of rat parotid acinar cells by the muscarinic cholinergic receptor agonist methacholine results in the formation of inositol 1,4,5-trisphosphate [1,4,5)IP3) and inositol cyclic 1:2,4,5-trisphosphate [c1:2,4,5)IP3) which, after 40 min, accumulate to a ratio of 1:0.57. The turnover rates of these inositol trisphosphates have been determined in cholinergically stimulated rat parotid cells by measuring the degradation of the 3H-labeled compounds following receptor blockade. (1,4,5)IP3 is rapidly metabolized, with a half-time of 7.6 s; (c1:2,4,5)IP3 declines much more slowly with a half-time of almost 10 min. Because the formation and metabolism of (c1:2,4,5)IP3 are so slow, (c1:2,4,5)IP3 gradually accumulates upon prolonged receptor activation. Inositol trisphosphate turnover was compared to the receptor-mediated changes in cytoplasmic Ca2+ concentration, as measured by the fluorescent Ca2+ indicator, fura-2. The Ca2+ signal decays upon termination of inositol phosphate formation and returns to base line within 30 s. Thus, while (c1:2,4,5)IP3 may have some yet unknown biological effects on Ca2+ homeostasis, its metabolism seems far too slow to be the primary regulator of cytosolic Ca2+ levels under long term stimulatory conditions. The rate at which the Ca2+ signal decays is, however, somewhat slowed after prolonged agonist stimulation. Furthermore, the capacity of the cells to mobilize intracellular Ca2+ in response to a second agonist stimulation is slightly delayed when the duration of the first stimulus is prolonged. The results suggest that the regulation of cytoplasmic Ca2+ levels may be more complicated than initially realized and could depend on the combined actions of more than one inositol polyphosphate.

Animals↗
PubMed1987

Epidermal growth factor and angiotensin II stimulate formation of inositol 1,4,5- and inositol 1,3,4-trisphosphate in hepatocytes. Differential inhibition by pertussis toxin and phorbol 12-myristate 13-acetate.

The ability of epidermal growth factor (EGF) and angiotensin II to stimulate production of inositol trisphosphate and mobilize intracellular Ca2+ in hepatocytes was compared using quin2 fluorescence to monitor changes in Ca2+ levels and high performance liquid chromatography to resolve the inositol trisphosphate (InsP3) isomers. Both EGF and angiotensin II stimulated an increase in free intracellular Ca2+ concentration ([Ca2+]i) as well as a rapid increase in the production of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). Concentrations of angiotensin II which gave a rise in [Ca2+]i equivalent to that seen with maximal doses of EGF produced an equivalent increase in Ins(1,4,5)P3 formation. Both EGF and angiotensin II stimulated the formation of the Ins(1,3,4)P3 and inositol 1,3,4,5-tetrakisphosphate isomers. The formation of the Ins(1,3,4)P3 isomer lagged behind production of Ins(1,4,5)P3 but eventually reached higher levels in the cell. The initial rise in [Ca2+]i and InsP3 levels stimulated by EGF and angiotensin II was not affected by reducing the external Ca2+ concentration below 30 nM with an excess of [ethylenebis(oxyethylenenitrilo)] tetraacetic acid. Treatment of hepatocytes for 30-180 s with 1 micrograms/ml phorbol 12-myristate 13-acetate prior to the addition of EGF blocked the EGF-stimulated production of Ins(1,4,5)P3 and the increase in [Ca2+]i. Phorbol 12-myristate 13-acetate attenuated the production of Ins(1,4,5)P3 generated by angiotensin II over the concentration range of 10(-10) to 10(-8) M; however, the Ca2+ signal was only inhibited at the 10(-10) M dose of angiotensin II. Treatment of rats with pertussis toxin for 72 h prior to isolating hepatocytes blocked the ability of EGF to increase Ins(1,4,5)P3 and Ins(1,3,4)P3 but did not inhibit the ability of any concentration of angiotensin II to stimulate formation of InsP3 or inositol tetrakisphosphate. The observation that pertussis toxin selectively abolishes EGF-stimulated inositol lipid breakdown suggests that EGF and angiotensin II use different mechanisms to activate phospholipase C in hepatocytes.

Aminoquinolines↗
PubMed2006

scyllo-inositol pentakisphosphate as an analogue of myo-inositol 1,3,4,5,6-pentakisphosphate: chemical synthesis, physicochemistry and biological applications.

myo-Inositol 1,3,4,5,6-pentakisphosphate (Ins(1,3,4,5,6)P(5)), an inositol polyphosphate of emerging significance in cellular signalling, and its C-2 epimer scyllo-inositol pentakisphosphate (scyllo-InsP(5)) were synthesised from the same myo-inositol-based precursor. Potentiometric and NMR titrations show that both pentakisphosphates undergo a conformational ring-flip at higher pH, beginning at pH 8 for scyllo-InsP(5) and pH 9 for Ins(1,3,4,5,6)P(5). Over the physiological pH range, however, the conformation of the inositol rings and the microprotonation patterns of the phosphate groups in Ins(1,3,4,5,6)P(5) and scyllo-InsP(5) are similar. Thus, scyllo-InsP(5) should be a useful tool for identifying biologically relevant actions of Ins(1,3,4,5,6)P(5), mediated by specific binding sites, and distinguishing them from nonspecific electrostatic effects. We also demonstrate that, although scyllo-InsP(5) and Ins(1,3,4,5,6)P(5) are both hydrolysed by multiple inositol polyphosphate phosphatase (MINPP), scyllo-InsP(5) is not dephosphorylated by PTEN or phosphorylated by Ins(1,3,4,5,6)P(5) 2-kinases. This finding both reinforces the value of scyllo-InsP(5) as a biological control and shows that the axial 2-OH group of Ins(1,3,4,5,6)P(5) plays a part in substrate recognition by PTEN and the Ins(1,3,4,5,6)P(5) 2-kinases.

Inositol Phosphates↗
PubMed1998

Exogenous inositol and genes responsible for inositol transport are required for mating and sporulation in Shizosaccharomyces pombe.

Fission yeast, Schizosaccharomyces pombe, is a natural inositol auxotroph. We show here that the amount of exogenous inositol added to the medium is critical for the control of its life cycle. Above growth-limiting concentrations inositol stimulates mating and sporulation in minimal medium. The effect of inositol is also observed on yeast-extract-medium plates. We selected a mutant, IM49, which mates and sporulates only poorly and show that it is defective in inositol transport. Its defect is in a gene (itr2) coding for a putative 12 membrane-spanning protein. The polypeptide contains the two sugar-transport motifs typical for hexose transporters and shows good homology to the two Saccharomyces cerevisiae inositol transporters. The itr2 gene is essential for cell growth and its mRNA level is repressed by glucose. Mutant IM49 is also complemented by a multicopy suppressor gene (itr1) which codes for a putative hexose transporter with unknown substrate specifity.

Amino Acid Sequence↗
PubMed2006

A de novo approach to C-branched inositols: synthesis of a myo-inositol precursor for C-linked glycosyl phosphatidylinositols.

C-Linked glycosyl inositols are valuable structure-activity probes because of their greater hydrolytic stability and different conformational behavior compared with their parent O-glycosides. Simple C-branched inositols are synthetic precursors to these and other groups of inositol mimetics. Herein is described a de novo synthesis of C-branched inositols that contain a versatile ethenyl side chain for elaboration into more complex appendages. The approach centers on a stereoselective oxocarbenium ion-allylsilane cyclization and provides C-branched inositols with different stereochemical motifs. The synthesis of C-ethenyl-di-O-isopropylidene-myo-, neo-, epi-, and allo-inositols is discussed.

Carbohydrate Conformation↗
PubMed1999

Effects of a water-soluble antitumor ether phosphonoinositide, D-myo-inositol 4-(hexadecyloxy)-3(S)-methoxybutanephosphonate (C4-PI), on inositol lipid metabolism in breast epithelial cancer cell lines.

We have demonstrated previously that D-myo-inositol 4-(hexadecyloxy)-3(S)-methoxybutanephosphonate (C4-PI), an isosteric phosphonate analog of phosphatidylinositol developed to inhibit inositol lipid metabolism, was unable to inhibit phosphatidylinositol (PI) 3-kinase activity. We now report the effects of the compound on other aspects of inositol metabolism. We demonstrated that C4-PI inhibits the activity of purified recombinant PI-phospholipase C-beta (PLC-beta) at all concentrations tested; it enhanced the activity of PI-PLC-gamma and PI-PLC-delta at low concentrations (10 microM), while severely inhibiting their activities at higher concentrations. In the breast cancer cell lines MCF-7 (estrogen receptor positive) and MDA-MB-468 (estrogen receptor negative), C4-PI had no effect on the uptake of D-myo-inositol but severely inhibited its incorporation into PI. In spite of the drastic decrease in PI synthesis, C4-PI did not affect the levels of inositol incorporated into phosphatidylinositol 4,5-bisphosphate (PIP2) in the cells. In vitro assays showed that C4-PI inhibited PI synthase activity (inhibition of 35% at 50 microM) but had little effect on PI 4-kinase activity (inhibition of 13% at 150 microM). C4-PI inhibited the proliferation of MCF-7 and MDA-MB-468 cell lines with IC(50) values of 12 and 18 microM. Taken together, the results suggest that the accumulation of [3H]inositol in PIP2 in cells incubated with C4-PI may be due to the inhibition of PIP2 hydrolysis in the cells with no effect on its synthesis. The role of these C4-PI-induced effects in the mechanism of growth inhibition by C4-PI remains to be established.

Antineoplastic Agents↗
PubMed1976

Selectively blocked derivatives of muco-inositol and their conversion into derivatives of epi- and cis-inositol.

Benzylation, and then hydrolysis, of 1, 2:4, 5-di-O-isopropylidene-muco-inositol (1) gave 3, 6-di-O-benzyl-muco-inositol (3). This was converted into a series of derivatives, including the 1, 5-di-O-benzoyl-3, 6-di-O-benzyl-2, 4-di-p-toluenesulfonate 7. The resistance to displacement of the sulfonate groups in 7 prevented conversion of 7 into an intermediate for the synthesis of aminoglycoside antibiotics. Monobenzylation of 1, followed by an oxidation-reduction cycle, yielded 6-O-benzyl-1, 2:4, 5-di-O-isopropylidene-epi-inositol (10). From this was synthesized a series of epi-inositol derivatives, analogous to the muco series but less complete. For derivatives of 1, 2:5, 6-di-O-isopropylidene-epi- and muco-inositol, the p. m. r. data indicate modified skew conformations. The reaction of the 3, 6-di-p-bromobenzenesulfonate (17) of 1 with anhydrous hydrazine proceeded in part by S-O cleavage to regenerate 1, and in part by displacement of both sulfonate groups by the same nitrogen atom. The resulting, novel 1, 4-epimino-cis-inositol was converted into further derivatives.

Aminoglycosides↗
PubMed2002

Synthesis of D- and L-myo-inositol 2,4,5-trisphosphate and trisphosphorothioate: structural analogues of D-myo-inositol 1,4,5-trisphosphate.

The preparation of D- and L-myo-inositol 2,4,5-trisphosphate is described, together with the phosphorothioate counterparts. The known chiral diols D- and L-1,4-di-O-benzyl-5,6-bis-O-p-methoxybenzyl-myo-inositol were regioselectively protected at the 3-position using a benzyl group via a 2,3-O-stannylene acetal. Removal of the p-methoxybenzyl groups of each enantiomer gave D- and L-1,3,6-tri-O-benzyl-myo-inositol. Phosphitylation with bis(benzyloxy)diisoproplyaminophosphine and 1H-tetrazole gave the trisphosphite intermediate for each enantiomer. Oxidation with 3-chloroperoxybenzoic acid gave the fully protected D- and L-myo-inositol 2,4,5-trisphosphates. Sulphoxidation of the D- and L-2,4,5-trisphosphite intermediates gave the fully protected D- and L-myo-inositol 2,4,5-trisphosphorothioate compounds. The fully protected trisphosphates were deblocked using hydrogenolysis and the phosphorothioates were deprotected using sodium in liquid ammonia. The individual compounds were then purified using ion exchange chromatography to afford pure D- and L-myo-inositol 2,4,5-trisphosphates together with the corresponding phosphorothioates.

Inositol 1,4,5-Trisphosphate↗
PubMed2003

Determination of urinary myo-inositol concentration by an improved enzymatic cycling method using myo-inositol dehydrogenase from Flavobacterium sp.

BACKGROUND: To determine myo-inositol more accurately, we improved the enzymatic cycling method. METHODS: We screened myo-inositol dehydrogenase (MIDH; EC.1.1.1.18) from Flavobacterium sp., which was highly specific to myo-inositol. We measured urinary myo-inositol/creatinine ratio 2 h after 75-g oral glucose tolerance test (2 h MI) of 71 volunteers, and investigated the relationship between diabetes and urinary myo-inositol concentration. RESULTS: The calibration curve was linear (r = 1.00) up to 2000 micromol/l, and the detection limit was 10 micromol/l. Within-run and between-run CVs were 0.5-1.1% and 0.4-1.3%, respectively. The 2 h MI of impaired fasting glycemia (IFG; 65.1 +/- 46.6 mg/g Cr, P < 0.005), impaired glucose tolerance (IGT; 85.0 +/- 73.7 mg/g Cr, P < 0.001) and diabetes (163.4 +/- 73.7 mg/g Cr, P < 0.0001) increased significantly compared with that of normal glucose tolerance (NGT; 24.0 +/- 14.4 mg/g Cr). From receiver operating characteristic analyses on 2 h MI, with 50 mg/g Cr as a tentative cutoff value to detect diabetes, the sensitivity and specificity were 100% and 77%, respectively. With 40 mg/g Cr as a tentative cutoff value to detect NGT, the sensitivity and specificity were 74% and 85%, respectively. CONCLUSIONS: The myo-inositol measurement method demonstrated high specificity and yielded accurate results. The results of clinical trials suggested that 2 h MI could not only determine diabetes but also distinguish IFG and IGT from NGT.

Adult↗
PubMed2002

Facile syntheses of all possible diastereomers of conduritol and various derivatives of inositol stereoisomers in high enantiopurity from myo-inositol.

Phosphoinositide-based signaling processes are crucially important in intracellular signal transduction events. Inositol phosphate analogues have been useful in probing the structure-activity relationships between inositol phosphates and biomacromolecules, and in studying biological functions of newly found inositol phosphates. Thus, a systematic and ready access to inositol stereoisomers is highly desirable. And practical and convenient syntheses of conduritols and related compounds are also important because of their biological activities and their synthetic utilities in the preparation of other bioactive molecules. We herein report the first syntheses of all possible diastereomers of conduritol and various derivatives of eight inositol stereoisomers in high enantiopurity from myo-inositol, which involve efficient enzymatic resolution of the intermediates conduritol B and C derivatives, followed by oxidation-reduction or the Mitsunobu reaction, and cis-dihydroxylation in stereo- and regioselective manners.

Candida↗
PubMed1984

The contribution of inositol exchange to agonist-stimulated breakdown of myo- [2-3H] inositol-labelled phosphatidylinositol in mouse exocrine pancreas.

Agonists stimulate the release of myo-inositol from phosphatidylinositol (PtdIns) labelled in vivo with myo-[2-3H] inositol. In the presence of lithium, which inhibits myo-inositol-1-phosphatase, the compound which accumulates following the breakdown of pre-labelled PtdIns is inositol-1-phosphate. This indicates that the agonist-stimulated release of the head group from this lipid is not the result of inositol exchange and is due to phosphodiesterase activity. The total amount of 3H-labelled compounds released from PtdIns in the presence and absence of lithium is the same, which indicates the labelled compounds which are released are not re-incorporated. Agonist-induced release of myo-[2-3H] inositol can be used as a reliable indication of PtdIns breakdown in the exocrine pancreas.

Animals↗
PubMed1996

Effect of inositol 1,3,4,5-tetrakisphosphate on inositol trisphosphate-activated Ca2+ signaling in mouse lacrimal acinar cells.

In mouse lacrimal acinar cells, microinjection of the metabolically stable analog of inositol 1,4,5-trisphosphate, inositol 2,4,5-trisphosphate ((2,4,5)IP3), stimulated both intracellular Ca2+ mobilization and Ca2+ entry. Microinjection of inositol 1,3,4,5-tetrakisphosphate ((1,3,4,5)IP4), the inositol 1,4,5-trisphosphate-3-kinase product, was ineffective at mobilizing intracellular Ca2+ or activating Ca2+ entry. In lacrimal cells previously microinjected with submaximal levels of (2,4,5)IP3, the subsequent microinjection of low to moderate concentrations of (1,3,4,5)IP4 did not result in additional release of intracellular Ca2+, nor did it potentiate the Ca2+ entry phase attributable to (2,4,5)IP3. However, as previously demonstrated (Bird, G. S. J., Rossier, M. F., Hughes, A. R., Shears, S. B., Armstrong, D. L., and Putney, J. W., Jr. (1991) Nature 352, 162-165), additional injections of (2,4,5)IP3 induced further mobilization of intracellular Ca2+ and increased the elevated and sustained Ca2+ entry phase. Introduction of high concentrations of (1,3,4,5)IP4 appeared to inhibit or block the (2,4,5)IP3-induced Ca2+ entry phase. These results were consistent with the observed effect of (1,3,4,5)IP4 in permeabilized lacrimal cells, where (1,3,4,5)IP4 did not release cellular 45Ca2+ but at high concentrations inhibited the ability of submaximal concentrations of (2,4,5)IP3 to release 45Ca2+. Likewise, injection of a high concentration of (1,3,4,5)IP4 prior to injection of (2,4,5)IP3 blocked both release and influx of Ca2+. The inhibitory action of (1,3,4,5)IP4 on Ca2+ signaling observed in intact cells occurred at concentrations that might be obtained in agonist-stimulated cells. However, in permeabilized cells, (1,3,4,5)IP4 inhibited Ca2+ mobilization at concentrations exceeding those likely to occur in agonist-stimulated cells. These results suggest that physiologically relevant levels of (1,3,4,5)IP4 in the cell cytoplasm do not release Ca2+, nor do they potentiate inositol trisphosphate-induced Ca2+ entry across the plasma membrane. Rather, the possibility is raised that (1,3,4,5)IP4 or one of its metabolites could function as a negative feedback on Ca2+ mobilization by inhibiting inositol 1,4,5-trisphosphate-induced Ca2+ release.

Animals↗