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PubMed1987

Cross-linking membrane IgM induces production of inositol trisphosphate and inositol tetrakisphosphate in WEHI-231 B lymphoma cells.

The addition of anti-IgM to the immature B lymphoma cell line WEHI-231 resulted in breakdown of phosphatidylinositol 4,5-bisphosphate, generating diacylglycerol and inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). These reactions have recently been demonstrated in mature resting B cells stimulated with anti-IgM, as well. In addition to Ins(1,4,5)P3, inositol tetrakisphosphate (InsP4) and inositol 1,3,4-trisphosphate (Ins(1,3,4)P3) were rapidly generated in WEHI-231 cells upon stimulation of the antigen receptor with anti-IgM. These two inositol polyphosphates are probably generated from Ins(1,4,5)P3 by phosphorylation to yield InsP4 and removal of the 5-phosphate from InsP4 to yield Ins(1,3,4)P3. It is possible that these inositol polyphosphates play a second messenger role in mediating the biologic effects of antigen-receptor signaling. It had previously been shown that anti-IgM also causes an increase in cytoplasmic free calcium. Therefore, the relationship between Ca2+ elevation and phosphoinositide breakdown was investigated. Although elevation of cytoplasmic Ca2+ with ionophores can trigger phosphoinositide breakdown, this required levels of Ca2+ well beyond those normally seen in response to anti-IgM. Thus, the Ca2+ elevation seen in response to anti-IgM cannot be the event controlling phosphoinositide breakdown. WEHI-231 cells have been shown to have a calcium storage compartment that releases Ca2+ in the presence of Ins(1,4,5)P3; therefore, it is likely that anti-IgM stimulates phosphoinositide breakdown as a primary event and this leads to the elevation of cytoplasmic Ca2+.

Animals↗
PubMed1987

Early production of 1,4,5-inositol trisphosphate and 1,3,4,5-inositol tetrakisphosphate by histamine and carbachol in ileal smooth muscle.

We have examined the time course of the formation of inositol mono-, bis-, tris, and tetrakisphosphates (InsP1, InsP2, InsP3, and InsP4, respectively) in slices of the longitudinal muscle of guinea pig small intestine that had been prelabeled with myo-3H-inositol. The agonists employed were histamine and carbachol. InsP3 increases immediately with a time course which is similar to that of the increase in contractile force and remains elevated for the rest of the incubation period. High performance liquid chromatography analysis revealed that InsP3 is composed of two isomers, the 1,4,5- and 1,3,4-isomers. The release of 1,4,5-inositol trisphosphate [Ins(1,4,5)P3] was followed by the rapid accumulation of InsP4 and later on by the formation of 1,3,4-inositol trisphosphate [Ins(1,3,4)P3]. Ins(1,3,4)P3 and InsP4 were identified by co-chromatography with the Ins(1,3,4)P3 and 1,3,4,5-inositol tetrakisphosphate prepared from 3H-Ins(1,4,5)P3 using a kinase from rat brain. The time course of accumulation of these compounds is consistent with a second messenger role of Ins(1,4,5)P3 in initiation of smooth muscle contraction.

Animals↗
PubMed1994

Osmoregulatory alterations in myo-inositol uptake by bovine lens epithelial cells. Part 4: Induction pattern of Na(+)-myo-inositol cotransporter mRNA under hypertonic conditions denoting an early-onset, interactive, protective mechanism against water stress.

PURPOSE: To examine the effect of hypertonicity on the induction of the Na(+)-myo-inositol (Na(+)-MI) cotransporter(s) in cultured bovine lens epithelial cells (BLECs). METHODS: Na(+)-MI cotransporter 626-bp reverse transcription-polymerase chain reaction product amplified from lens cell RNA and aldose reductase (AR) cDNA probes were used to measure respective mRNA content by Northern blot analysis. RESULTS: Northern blot analysis of BLEC mRNA hybridized to Na(+)-MI cotransporter cDNA showed that Na(+)-MI cotransporter mRNA increased when secondary cultures of BLECs were exposed to physiological medium supplemented with 116 mmol/l NaCl. A time course further revealed a maximal increase in Na(+)-MI cotransporter mRNA by 8 hours. Thereafter, the level of Na(+)-MI cotransporter mRNA steadily declined for the duration of the 72-hour incubation period despite continuous exposure of BLECs to hypertonicity. AR mRNA levels maximally increased by 24 h of cell exposure to hypertonic condition. Unlike Na(+)-MI cotransporter mRNA, AR mRNA remained elevated throughout the duration of the experiment. Hypertonic exposure resulted in a steady state accumulation of myo-inositol and sorbitol for 6 days. Inhibition of sorbitol formation prompted the intracellular myo-inositol content to a higher level. CONCLUSIONS: These data suggest that enhanced MI transport and accumulation, as an adaptive osmoregulatory response to hypertonicity in cultured BLECs, is a primary, early-onset, protective mechanism against water stress, succeeded by, enhanced sorbitol formation and accumulation, a secondary, late-onset protective mechanism. The lens appears to respond to the preliminary stages of hyperosmotic stress by induction of Na(+)-MI cotransporter mRNA, indicating that the myo-inositol carrier protein(s) play an initial responsive role in the management of osmotic stress. Lens water stress management is interactive because myo-inositol and sorbitol levels are regulated in concert.

Aldehyde Reductase↗
PubMed1994

Osmoregulatory alterations in myo-inositol uptake by bovine lens epithelial cells. Part 1: A hypertonicity-induced protein enhances myo-inositol transport.

PURPOSE: The nature of the association between attenuated myo-inositol-concentrating capability, intracellular polyol accumulation, and hypertonicity-enhanced myo-inositol uptake was investigated in cultured bovine lens epithelial cells (BLECs) exposed to high ambient galactose. METHODS: The kinetic characteristics of myo-inositol accumulation based on the measurement of in vitro myo-[3H]inositol (3H-MI) uptake was determined with cultured BLECs incubated in either high ambient galactose or galactose-free, physiological medium under experimental conditions that included both aldose reductase inhibition and elevation of extracellular osmotonicity. RESULTS: The uptake of 3H-MI was lowered after chronic (20 hour) preincubation of cultured BLECs in 40 mmol/l galactose (i.e., conditions that would favor galactitol synthesis) compared with control cells in galactose-free, physiological medium. Acute exposure (3 hours) of cultured BLECs to a range of 10 to 40 mmol/l galactitol or 5.5 to 44 mmol/l galactose plus the aldose reductase inhibitor (ARI), sorbinil, established by Dixon plot that galactitol, but not galactose, inhibited both the high- and the low-affinity MI transport sites. MI uptake was markedly stimulated in cultured BLECs exposed to galactose-free, hyperosmotic medium by the addition of extracellular raffinose, mannitol, or sorbitol for 20 hours. The enhanced uptake involved increase in the maximal velocity without significant change in Km of both the high- and low-affinity MI transport sites, as indicated by Lineweaver-Burk analysis. However, a similar coadministration of 150 mmol/l sorbitol to the 40 mmol/l galactose (Gal) medium significantly increased, but failed to normalize, the MI uptake relative to that observed with galactose-free, physiological medium. The combined administration of 150 mmol/l sorbitol and the ARI, zopolrestat, to Gal significantly exceeded the MI uptake observed with physiological medium. Exposure of BLECs to cycloheximide for 20 hours did not affect MI uptake in cells maintained in 40 mmol/l galactose but inhibited the otherwise enhanced MI uptake in cells maintained in Gal plus 150 mmol/l sorbitol and zopolrestat in the omission versus the inclusion of cycloheximide. CONCLUSIONS: These results suggest that bovine lens epithelial cells respond to hypertonic stress by elevating myo-inositol transport activity. The increase in MI uptake is due to an increase in the number (or, possibly, a change in the transporter turnover rate) of high- and low-affinity, sodium-dependent MI transporters expressed as a result of the osmotic shock stemming from exposure to hypertonic medium.

Aldehyde Reductase↗
PubMed2004

D-6-Deoxy-myo-inositol 1,3,4,5-tetrakisphosphate, a mimic of d-myo-inositol 1,3,4,5-tetrakisphosphate: biological activity and pH-dependent conformational properties.

D-6-Deoxy-myo-inositol 1,3,4,5-tetrakisphosphate [D-6-deoxy-Ins(1,3,4,5)P(4)] 3 is a novel deoxygenated analogue of D-myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)] 2, a central and enigmatic molecule in the polyphosphoinositide pathway of cellular signalling. D-6-Deoxy-Ins(1,3,4,5)P(4) is a moderate inhibitor of Ins(1,4,5)P(3) 5-phosphatase [1.8microM] compared to Ins(1,3,4,5)P(4) [0.15microM] and similar to that of L-Ins(1,3,4,5)P(4) [1.8microM]. In displacement of [(3)H] Ins(1,4,5)P(3) from the rat cerebellar Ins(1,4,5)P(3) receptor, while slightly weaker [IC(50)=800nM] than that of D-Ins(1,3,4,5)P(4) [IC(50)=220nM], 3 is less markedly different and again similar to that of L-Ins(1,3,4,5)P(4) [IC(50)=660nM]. 3 is an activator of I(CRAC) when inward currents are measured in RBL-2H3-M1 cells using patch-clamp electrophysiological techniques with a facilitation curve different to that of Ins(1,3,4,5)P(4). Physicochemical properties were studied by potentiometric (31)P and (1)H NMR titrations and were similar to those of Ins(1,3,4,5)P(4) apart from the observation of a biphasic titration curve for the P1 phosphate group. A novel vicinal phosphate charge-induced conformational change of the inositol ring above pH 10 was observed for D-6-deoxy-Ins(1,3,4,5)P(4) that would normally be hindered because of the central stabilising role played by the 6-OH group in Ins(1,3,4,5)P(4). We conclude that the 6-OH group in Ins(1,3,4,5)P(4) is crucial for its physicochemical behaviour and biological properties of this key inositol phosphate.

Calcium Channels↗
PubMed1989

Inositol 1:2-cyclic,4,5-trisphosphate is only a weak agonist at inositol 1,4,5-trisphosphate receptors.

The activity of inositol 2,4,5-trisphosphate and inositol 1:2-cyclic,4,5-trisphosphate relative to inositol 1,4,5-trisphosphate was examined by two assays; firstly, in a binding assay using rat cerebellar membranes, and secondly, in a Ca2+-mobilization assay using permeabilized Swiss 3T3 cells. In both assays the first two phosphates have a potency at least an order of magnitude less than inositol 1,4,5-trisphosphate. The possible reasons for differences between these results and previous data are discussed, as are the implications for any putative physiological role for the cyclic trisphosphate.

Animals↗
PubMed2000

Expression level of inositol trisphosphate and inositol tetrakisphosphate receptors and their influence on Ca2+ release in permeabilized HL-60 and T15 cells.

To try to further define the mechanism of action of the putative second messenger inositol 1,3,4,5-tetrakisphosphate (InsP4), we have studied its effects in permeabilized cells expressing different levels of inositol trisphosphate receptor (InsP3R) types I and III and of the GTPase-activating protein GAP1IP4BP. During the growth curve of human HL-60 cells and mouse T15 cells there was an increase in these proteins, which was further increased by differentiation (HL-60) and, marginally, by transformation (T15). T15 cells entering the stationary phase showed much lower concentrations of these proteins and expression was below detection in apoptotic HL-60 cells. Rasp21 showed a different pattern of expression. The ratios of InsP3R subtypes seem to affect the dose-response curve for inositol 2,4,5-trisphosphate Ins(2,4,5)P3. In permeabilized T15 cells the curve was approximately 5-fold to the right of that obtained using HL-60 cells. However, permeabilized untreated and differentiated HL-60 cells and T15 cells all showed a comparable synergistic effect of InsP4 on Ca2+ release stimulated by a concentration of Ins(2,4,5)P3, releasing approximately 20% of the Ins(1,4,5)P3 sensitive Ca2+ pool. The data indicate that under these conditions InsP4 is acting independently of cell type, of the ratio of inositol trisphosphate receptor subtypes, and of the concentration of GAP1IP4BP.

Animals↗
PubMed1988

Turnover of inositol phospholipids in cultured murine keratinocytes: possible involvement of inositol triphosphate in cellular differentiation.

The relationship between the turnover of inositol phospholipids (PtdIns) and the growth and differentiation of normal murine keratinocytes in culture was studied. Addition of myo-[U-14C]inositol to freshly plated cells resulted in a linear incorporation of radiolabel into the inositol phospholipids of the proliferating basal cells in culture during the initial 36 h, after which time the rate of radiolabel incorporation into the cells declined. The decrease in the incorporation of the radiolabel into the PtdIns, particularly the more highly phosphorylated PtdIns-4P and PtdIns4,5P2, correlated with the marked hydrolysis of these polyphosphoinositides and the rapid hydrolytic release of the inositol phosphates (InsP2 and InsP3). The transient accumulation of the InsPs correlated with the onset of differentiation of these cells. To ascertain whether the above observations of keratinocytes that were undergoing normal proliferative and differentiating phases in culture are consistent with the more synchronized populations of proliferative and differentiating cells, we investigated the turnover of PtdIns in a Ca2+-regulated system of homogenous populations of proliferating mouse keratinocytes in 0.09 mM Ca2+, and a differentiating population in 1.8 mM Ca2+. Our data from system revealed rapid hydrolysis of the PtdIns in the prelabeled low-Ca2+ proliferating cells immediately after a switch from the low to normal extracellular Ca2+ medium. Associated with this hydrolysis was the rapid and transient accumulation of the InsPs (maximum of 60 sec). The hydrolysis of the PtdIns and the accumulation of the InsP3 were not observed when the prelabeled proliferating cells were switched from a low to a low extracellular Ca2+ medium. These results suggest that the rapid hydrolysis of the PtdIns, particularly PtdIns4,5P2, which was accompanied by the hydrolytic release of InsP3, could be the initiating signal to program proliferating keratinocytes into differentiation.

Animals↗
PubMed1994

Phosphorylation of inositol 1,4,5-trisphosphate analogues by 3-kinase and dephosphorylation of inositol 1,3,4,5-tetrakisphosphate analogues by 5-phosphatase.

A series of 32P-labeled D-myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] analogues was enzymically prepared from the corresponding D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] analogues using recombinant rat brain Ins(1,4,5)P3 3-kinase and [gamma-32P]ATP. Ins(1,4,5)P3 analogues with bulky groups at the 2-OH position, substitutions of phosphates by thiophosphates and D-6-deoxy-myo-Ins(1,4,5)P3 were tested. Using [3H]Ins(1,4,5)P3 and ATP gamma S, a [3H]Ins(1,3,4,5)P4 analogue with a thiophosphate at the D-3 position was prepared. The D-4 and/or D-5 phosphate group seemed to be important for 3-kinase activity, while the OH group at position 6 was not crucial. The addition of bulky groups at the 2-OH position did not prevent phosphorylation. The labeled Ins(1,3,4,5)P4 analogues were purified and their degradation by type-I Ins(1,4,5)P3/Ins(1,3,4,5)P4 5-phosphatase was compared with the degradation of Ins(1,3,4,5)P4. Substitution of the phosphate group at positions 1 or 3 by a thiophosphate, or the addition of bulky groups at the 2-OH position did not prevent degradation. D-6-Deoxy-myo-inositol 1,3,4,5-tetrakisphosphate could not be degraded by the 5-phosphatase, indicating the importance of the 6-OH group for 5-phosphatase action. D-6-Deoxy-myo-inositol 1,3,4,5-tetrakisphosphate could be an important tool in elucidating the cellular functions of Ins(1,3,4,5)P4.

Adenosine Triphosphate↗
PubMed1990

Lacrimal gland inositol trisphosphate isomer and inositol tetrakisphosphate production.

In the lacrimal gland, cholinergic agonists stimulate protein and electrolyte/water secretion by producing inositol trisphosphate (IP3) from phosphatidylinositol bisphosphate. To determine which IP3 isomers were produced and whether inositol tetrakisphosphate (IP4) was produced during activation of secretion, rat exorbital gland acini were [3H]inositol-labeled and stimulated by the cholinergic agonist carbachol. Water-soluble inositol phosphates were separated by anion-exchange chromatography using Dowex columns or high-performance liquid chromatography. Intracellular Ca2+ concentration ([Ca2+]i) was measured by fluorescence using the Ca2+ dye fura-2. Carbachol (10(-3) M) produced a time-dependent increase in 1,4,5-IP3, 1,3,4-IP3, and 1,3,4,5-IP4 levels during 0-60 s of stimulation. The 1,4,5-IP3 level increased rapidly and was followed by a slower rise in 1,3,4-IP3 and 1,3,4,5-IP4 levels. A 3-s carbachol (10(-8) to 10(-2) M) stimulation caused a concentration-dependent rise in the 1,4,5-IP3 level. Carbachol (10(-9) to 10(-2) M) increased [Ca2+]i in a concentration-dependent manner. Carbachol (10(-3) M) increased [Ca2+]i to a maximum level by 10 s; by 60 s [Ca2+]i decreased by 38%. The maximum increase in 1,4,5-IP3 levels occurred at a higher carbachol concentration than the increase in [Ca2+]i or protein secretion. We concluded that cholinergic stimulation of the lacrimal gland rapidly increased 1,4,5-IP3 levels, which was responsible for the initial increase in [Ca2+]i and initial rapid phase of protein and fluid secretion. Cholinergic stimulation also increased 1,3,4-IP3 and 1,3,4,5-IP4, but more slowly; either acting alone or with 1,4,5-IP3, they could account for the slower phase of secretion.

Animals↗
PubMed1993

Adhesion to fibronectin stimulates inositol lipid synthesis and enhances PDGF-induced inositol lipid breakdown.

The aim of these experiments was to investigate whether inositol lipids might mediate some of the effects of extracellular matrix (ECM) on cellular form and functions. The lipid phosphatidylinositol bisphosphate (PIP2) plays a role in cytoskeletal regulation while its hydrolysis products, diacylglycerol and inositol triphosphate, serve as second messengers. We therefore measured the effect of adhesion to fibronectin (FN) on PIP2 and its hydrolysis products, in the presence and absence of the soluble mitogen PDGF. PDGF induced a threefold increase in release of water-soluble inositol phosphates in C3H 10T1/2 fibroblasts when cells were attached to FN, but had little effect in suspended cells. Suppression of inositol phosphate release in unattached cells was not due to dysfunction of the PDGF receptor or failure to activate phospholipase C-gamma; PDGF induced similar tyrosine phosphorylation of PLC-gamma under both conditions. By contrast, the total mass of phosphatidylinositol bisphosphate (PIP2), the substrate for PLC-gamma, was found to decrease by approximately 80% when cells were detached from their ECM attachments and placed in suspension in the absence of PDGF. PIP2 levels were restored when suspended cells were replated on FN, demonstrating that the effect was reversible. Furthermore, a dramatic increase in synthesis of PIP2 could be measured in cells within 2 min after reattachment to FN in the absence of PDGF. These results show that FN acts directly to stimulate PIP2 synthesis, and that it also enhances PIP2 hydrolysis in response to PDGF. The increase in PIP2 induced by adhesion may mediate some of the known effects of FN on cell shape and cytoskeletal organization, while regulation of inositol lipid hydrolysis may provide a means for integrating hormone- and ECM-dependent signaling pathways.

Animals↗
PubMed1968

Inositol Metabolism in Plants. V. Conversion of Myo-inositol to Uronic Acid and Pentose Units of Acidic Polysaccharides in Root-tips of Zea mays.

The metabolism of myo-inositol-2-(14)C, d-glucuronate-1-(14)C, d-glucuronate-6-(14)C, and l-methionine-methyl-(14)C to cell wall polysaccharides was investigated in excised root-tips of 3 day old Zea mays seedlings. From myo-inositol, about one-half of incorporated label was recovered in ethanol insoluble residues. Of this label, about 90% was solubilized by treatment, first with a preparation of pectinase-EDTA, then with dilute hydrochloric acid. The only labeled constituents in these hydrolyzates were d-galacturonic acid, d-glucuronic acid, 4-O-methyl-d-glucuronic acid, d-xylose, and l-arabinose, or larger oligosaccharide fragments containing these units. Medium external to excised root-tips grown under sterile conditions in myo-inositol-2-(14)C contained labeled polysaccharide.When label was supplied in the form of d-glucuronate, the pattern of labeled uronic acid and pentose units in cell wall polysaccharides resembled that obtained from labeled myo-inositol, indicating that both substances were metabolized along a common path during polysaccharide formation, and that methylation occurred at a step subsequent to uronic acid formation. When label was supplied in the form of l-methionine-methyl-(14)C, 4-O-methyl-d-glucuronic acid was the only labeled monosaccharide component that survived enzymatic or acid hydrolysis.Zea mays endosperm, a known source of phytin, developed maximal phytase activity after the third day of germination. Results obtained here suggest that myo-inositol released by hydrolysis of phytin represents the initial precursor of a normal, possibly predominant pathway for the formation of uronic acids in plants.

Journal Article↗
PubMed1990

Inositol tetrakisphosphate-induced sequestration of Ca2+ replenishes an intracellular pool sensitive to inositol trisphosphate.

In a permeable neoplastic rat liver epithelial (261B) cell system, inositol 1,3,4,5-tetrakisphosphate--Ins(1,3,4,5)P4--induces sequestration of Ca2+ released by inositol 2,4,5-trisphosphate--Ins(2,4,5)P3; a non-metabolized inositol trisphosphate (InsP3) isomer--and Ca2+ added exogenously in the form of CaCl2. Studies were performed to identify the Ca2+ pool filled after Ins(1,3,4,5)P4 treatment. Both Ins(2,4,5)P3 and inositol 1,4,5-trisphosphate--Ins(1,4,5)P3--dose-dependently release Ca2+ from permeable 261B cells--Ins(1,4,5)P3 having a threefold greater potency--but differ in that Ca2+ released by Ins(1,4,5)P3 is readily sequestered, while the Ca2+ released by Ins(2,4,5)P3 is not. Maximal release of Ca2+ by 6 microM Ins(2,4,5)P3 blocked the action of Ins(1,4,5)P3, demonstrating that these two isomers influence the same intracellular Ca2+ pool through a shared membrane receptor. Addition of 2 microM Ins(2,4,5)P3 to discharge partially the Ca2+ pool reduced the amount of Ca2+ released by a maximal dose of Ins(1,4,5)P3 (2 microM). Ins(1,3,4,5)P4 combined with Ins(2,4,5)P3 produced a Ca2+ release and sequestration response, which replenished the InsP3-sensitive pool as indicated by a recovery of full Ca2+ release by 2 microM Ins(1,4,5)P3. Induction of Ca2+ sequestration by Ins(1,3,4,5)P4 occurred dose-dependently, with a half-maximal response elicited at a dose of 0.9 microM. Further studies of the effect of Ins(1,3,4,5)P4 apart from the influence of Ins(2,4,5)P3 using a model in which the Ca2+ levels are raised by an exogenous addition of CaCl2 showed that Ins(1,4,5)P3 released twice the amount of Ca2+ from the storage pool following Ins(1,3,4,5)P4-induced Ca2+ sequestration. These results demonstrate that the Ca2+ uptake induced by Ins(1,3,4,5)P4 preferentially replenishes the intracellular Ca2+ storage sites regulated by Ins(1,4,5)P3 and Ins(2,4,5)P3.

Animals↗
PubMed1987

Production of inositol trisphosphates and inositol tetrakisphosphate in stimulated pancreatic islets.

Glucose and carbamylcholine caused concentration-dependent increases in the production of total [3H]inositol phosphates in [3H]inositol-labelled rat pancreatic islets. When extracts from islets stimulated with glucose, carbamylcholine or depolarising concentrations of K+ were analysed using anion-exchange high performance liquid chromatography, increased production of [3H]Ins1,4,5-P3 was detected, and in addition, elevated levels of two other labelled compounds which co-chromatographed with Ins1,3,4-P3 and Ins1,3,4,5-P4. In the case of carbamylcholine and high K+, such an effect was apparent within 20 s, whereas glucose appeared to cause a delayed response. In the presence of 5 mM LiCl, the accumulation of Ins1,3,4-P3 was more marked. The presence of LiCl had no major influence on the levels of Ins1,4,5-P3 or Ins1,3,4,5-P4. It is suggested that the stimulation of pancreatic islets with glucose, carbamylcholine or high K+ results in the hydrolysis of inositol lipids with the production of Ins1,4,5-P3 and in addition, Ins1,3,4-P3 and Ins1,3,4,5-P4. The physiological functions of these novel inositol phosphates in islets remain to be established.

Animals↗
PubMed1994

Intracellular concentrations of inositol, glycerophosphoinositol and inositol pentakisphosphate increase during haemopoietic cell differentiation.

We have analysed the levels of soluble inositol metabolites in HL60 cells as they differentiate towards neutrophils in response to a combination of all-trans-retinoic acid and granulocyte colony-stimulating factor and towards monocytes in response to 1 alpha-25-dihydroxyvitamin D3. In both cases, differentiation was accompanied by increases in intracellular inositol (Ins), glycerophosphoinositol (GroPIns) and inositol pentakisphosphate (InsP5) concentrations. [GroPIns] reached a peak early in the differentiation of both neutrophils and monocytes and subsequently fell to about double the starting level as the cells acquired mature characteristics, and [InsP5] rose later. Similarly, neutrophils derived in culture by the spontaneous differentiation of myeloid blast cells contained increased levels of Ins, GroPIns and InsP5 when compared to their parental blast cells. We have also compared the inositol metabolites present in two pairs of cell lines which are representative of immature and mature B and T lymphocytes. The mature cells again contained the higher levels of GroPIns and InsP5. We have previously demonstrated increases in Ins, GroPIns and Ins(1,3,4,5,6)P5 levels during the differentiation of HL60 cells towards neutrophils in response to DMSO and of GroPIns during the monocytoid differentiation of normal primitive myeloid blast cells in response to PMA. These observations suggest that deacylation of phosphatidylinositol by a phospholipase A/lysophospholipase pathway, forming GroPIns and probably also regulatory arachidonate metabolites, has some role in haemopoietic cell differentiation. The reasons why Ins(1,3,4,5,6)P5 and Ins accumulate during haemopoietic differentiation remain unknown.

Cell Differentiation↗
PubMed1991

Stretch increases inositol trisphosphate and inositol tetrakisphosphate in cultured pulmonary vascular smooth muscle cells.

There are no reports of the effect of stretch on inositol phosphates in smooth muscle. Phosphoinositide and inositol phosphate metabolism was studied in cultured rat vascular smooth muscle cells subjected to stretching. The masses of inositol trisphosphate and tetrakisphosphate increased (+34 +/- 7% and +58 +/- 12%, respectively; p less than 0.001) after 25 s of a single 20% stretch and had returned to control levels by 45 s; phosphatidylinositol, phosphatidylinositol phosphate and bisphosphate did not change. Repetitive stretch did not alter the masses of any of the compounds. A single stretch also increased 45Ca2+ efflux (+52 +/- 5%, p less than 0.01). These data suggest that stretch of cultured vascular smooth muscle can elicit a rapid, short-lived increase in inositol phosphates, which may subsequently affect Ca2+.

Animals↗
PubMed1988

Metabolism of inositol-1,3,4,6-tetrakisphosphate to inositol pentakisphosphate in adrenal glomerulosa cells.

Angiotensin II stimulates rapid formation of inositol-1,4,5-trisphosphate (Ins-1,4,5-P3) in bovine adrenal glomerulosa cells. In addition to being rapidly metabolized to lower inositol phosphates, Ins-1,4,5-P3 is converted to Ins-1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4) and Ins-1,3,4-P3 which is in turn phosphorylated to a further Ins-P4 isomer, namely Ins-1,3,4,6-P4. In bovine adrenocortical cytosol [3H]Ins-1,3,4,5-P4 and [3H]Ins-1,3,4-P3 were converted to Ins-1,3,4,6-P4 and inositol pentakisphosphate (Ins-P5) in a metabolic sequence suggesting that unlike Ins-1,3,4,5-P4, Ins-1,3,4,6-P4 is a direct precursor of Ins-P5. Consistent with this assumption, [3H]Ins-1,3,4,6-P4 was converted to Ins-P5 in electropermeabilized adrenal glomerulosa cells. These findings demonstrate that Ins-1,3,4,6-P4 is an intermediate link between InsP3 metabolism and the higher inositol phosphates detected in several tissues.

Animals↗
PubMed2005

Synthesis of (+/-)-2-O-[4'-(N-9''-purinyl)butyl] myo-inositol 1,4,5-tris(phosphate), a potent full agonist at the D-myo-inositol 1,4,5-tris(phosphate) receptor.

Racemic 2-O-[4'(9''-N-purinyl)butyl] myo-inositol 1,4,5-tris(phosphate) 8 was synthesized starting from myo-inositol. Substitution of position 2 by an alkyl side chain was rendered possible by inversion of the chair conformation of the inositol ring by means of an orthoester. The final compound is a full agonist with the same order of potency as d-myo-inositol 1,4,5-tris(phosphate).

Adrenal Cortex↗