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PubMed2006

Convenient synthesis of 3- and 6-deoxy-D-myo-inositol phosphate analogues from (+)-epi- and (-)-vibo-quercitols.

Starting from (+)-epi- and (-)-vibo-quercitols readily produced by bioconversion of myo-inositol, some biologically interesting phosphate and polyphosphate analogues, including the Ins(1,4,5)P(3) derivatives of 3-deoxy- and 6-deoxy-D-myo-inositol, could be readily prepared in a conventional manner. In addition, chemical modification at C-2 of the 3-deoxy Ins(1,4,5)P(3) provided 2-epimer, and 2-deoxy and 2-deoxy-2-fluoro forms. Eight polyphosphate analogues obtained were assayed for biological activity against PDH-Pase and PDH-K, and G6Pase, but none proved positive.

Animals↗
PubMed1996

Circulating factors and insulin resistance. II. The action of the novel myo-inositol cyclic 1,2-inositol phosphate phosphoglycan insulin antagonist from human plasma in regulating pyruvate dehydrogenase phosphatase.

A novel low mol wt inositol phosphoglycan antagonist of insulin action of oxidative glucose metabolism in isolated rat adipocytes was partially purified from normal human plasma and shown to be increased in type II diabetic plasma. It was characterized chemically as a myo-inositol phosphoglycan containing a cyclic 1,2-phosphate. This antagonist, termed fraction V3, is now shown to inhibit the action of an inositol glycan insulin pH 2.0 mediator that stimulates pyruvate dehydrogenase phosphatase in a similar manner to insulin. In addition, fraction V3 inhibits stimulation of the pyruvate dehydrogenase (PDH) phosphatase by Mg2+, the enzyme's required metal, and by spermine, a polyamine. Fraction V3 does not inhibit active PDH itself. The inhibitory effect is dose dependent and apparently noncompetitive or nonsurmountable for the insulin inositol glycan pH 2.0 mediator, thus comparing kinetically with its insulin antagonistic action on intact adipocytes. Its inhibitory action on PDH phosphatase is dose dependent and competitive for Mg2+ stimulation of the phosphatase. Additionally, fraction V3 is shown to inhibit stimulation by Mg2+ of cloned recombinant PDH phosphatase catalytic subunit. Inhibition by fraction V3 of Mg(2+)-stimulated PDH phosphatase and its cloned catalytic subunit helps explain its mechanism of action to inhibit insulin-stimulated oxidative glucose metabolism in adipocytes and its potential clinical significance in insulin resistance.

Animals↗
PubMed1987

Multiple coupling of neurohormone receptors with cyclic AMP and inositol phosphate production in anterior pituitary cells.

Regulation of adenohypophyseal hormone secretions has been shown to involve cyclic AMP production, modulation of phosphatidyl inositol diphosphate breakdown and Ca2+ mobilization. Various neurohormone receptors are positively or negatively coupled to adenylate cyclase activity in anterior pituitary cells. The effects of these neurohormones on adenylate cyclase activity are consistent with the effect on hormone secretions, suggesting that modulation of the enzyme activity is actually involved in the regulation of adenohypophyseal secretions. Thus DA inhibits, whereas VIP stimulates adenylate cyclase activity of the same cell type, which, according to the effect of these neurohormones on prolactin secretion, appear to be lactotrophs. On the other hand, SRIF inhibits, whereas GRF stimulates the adenylate cyclase activity of another cell type, namely somatotrophs, whereas CRF appears to act on a third cell type, corticotrophs. Peripheral hormones have been shown to modulate the sensitivity of anterior pituitary cells to these neurohormones. Estradiol long-term treatment has an anti-dopaminergic effect on prolactin secretion. The steroid also suppresses the dopamine inhibition of adenylate cyclase. This effect appears selective to the DA inhibition, since AII inhibition of the enzyme is only partially reduced, whereas the somatostatin inhibition is markedly increased. Peripheral hormones seem to affect the sensitivity of adenohypophyseal cells not only by modulating the number of receptors for a given neurohormone but also by interfering with the coupling mechanisms of these receptors. AII and DA inhibit the adenylate cyclase activity of lactotroph cells. The prolactin stimulation induced by angiotensin is not consistent with the effect of the peptide on adenylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylate Cyclase Toxin↗
PubMed1991

Histamine-induced inositol phosphate accumulation in HeLa cells: lithium sensitivity.

1. In the presence of 10 mM Li+ the histamine-stimulated accumulation of [3H]-inositol monophosphates [( 3H]-IP1) in HeLa cells prelabelled with [3H]-inositol increased over 10-20 min to a plateau level, which was normally maintained up to 60 min. Levels of [3H]-inositol bis- and trisphosphates [( 3H]-IP2 and [3H]-IP3) initially increased rapidly but declined to near basal levels by 20 min. 2. The same pattern of histamine-induced [3H]-IP1 accumulation was observed in cells in which [3H]-inositol was present 30 min before and during the incubation with histamine. Concentration-response curves for histamine measured in the presence of 10 mM Li+ were closely similar in cells prelabelled for 24 h with [3H]-inositol and in cells exposed to [3H]-inositol for only 30 min before addition of histamine, without removing the [3H]-inositol. The EC50 for histamine was 1.6 +/- 0.2 microM. 3. [3H]-IP1 accumulation induced by a sub-maximal concentration of histamine, 1 microM, also reached a plateau, but at a lower level than with 1 mM histamine. 4. Addition of 10 mM NaF at the plateau phase of [3H]-IP1 accumulation induced by 1 mM histamine resulted in a further increase in the level of [3H]-IP1. The level of [3H]-IP1 in the presence of histamine + NaF was 1.4 +/- 0.2 fold of that of the sum of the responses to histamine and NaF acting alone (basal levels subtracted). 5. Addition of 1 microM mepyramine at the plateau phase of [3H]-IP1 accumulation induced by 1 mM histamine in the presence of 10mM Li + resulted in a decline in the level of [3H]-IP1, implying that the metabolism of [3H]-IP1 is not completely blocked by 10mM Li' in HeLa cells. 6. Omission of the 15 min preincubation period with 10mM Li+ before stimulation with 100 microM histamine for 15 min resulted in an approximate halving of the level of [3H]-IP1, without any significant change in basal accumulation. Periods of preincubation with 10mM Li' longer than 15min did not produce any further increase in the level of [3H]-IP1 induced by histamine. 7. Basal and histamine-induced levels of [3H]-IP, increased as the concentration of Li+ was increased from 0 to 60mm, but the effect on the histamine-induced response was greater than on the basal level. Increasing the concentration of Li+ from 0 to 60 mm had only a small and mostly statistically insignificant effects on the levels of [3H]-1P2 and [3H]-1P3. The EC50 for histamine-induced [3H]-4P1 accumulation in the presence of 30mm Li + was 2.4 +/- 0.4 microM. 8. The results indicate that IP1 metabolism in HeLa cells is much less sensitive to Li+ than in mammalian brain. The plateau phase of histamine-induced [3H]-IP1 accumulation in the presence of 10mM Li+ thus represents a steady-state level. On a simple model the plateau level will be proportional to the rate of [3H]-IP1 formation at that time. The lower the concentration of Li' present, the better the approximation will be. The information obtained is thus not the same as when [3H]-1P, metabolism is completely blocked, in which case [3H]-IP1 accumulated can be used to calculate a mean rate of formation over the whole of the incubation period.

Fluorides↗
PubMed1988

Identification and characterization of guinea pig angiotensin II ventricular and atrial receptors: coupling to inositol phosphate production.

Angiotensin II elicits a receptor-mediated positive inotropic response in cardiac tissue from most mammalian species by activating voltage-sensitive slow Ca2+ channels. In the guinea pig, we confirm there is no in vitro contractile force development in bioassay systems using isolated hearts or left atrial tissue in response to angiotensin peptides. However, 125I-angiotensin II binding sites that have the characteristics of a membrane receptor were identified in ventricular (myocardial) and atrial membrane preparations from guinea pigs. In ventricles, saturation-binding data yielded an optimal fit to a two-site model with a high-affinity site Kd1 = 3.6 +/- 0.7 nM and a low-affinity site Kd2 = 433 +/- 126 nM and binding capacities of 66 +/- 10 and 821 +/- 49 fmol/mg protein, respectively. In atria, saturation binding data yielded an optimal fit to a two-site model with a high-affinity site Kd1 = 1.6 nM and a low-affinity site Kd2 = 300 nM and capacities of 145 and 752 fmol/mg protein, respectively. The ventricular binding of 125I-angiotensin II was stimulated approximately twofold in the presence of the divalent cations calcium and magnesium (10 mM). Nonhydrolyzable analogues of guanosine triphosphate increased the dissociation rate of the bound 125I-angiotensin II and decreased hormone binding to the receptor at equilibrium. Competition for 125I-angiotensin II binding by an agonist-antagonist analogue series correlated with previous studies obtained in the rabbit, a mammal in which inotropic responses to angiotensin II were demonstrated. The data indicate the presence of angiotensin II myocardial and atrial receptors and a G-type coupling protein in guinea pig. Although this species lacks an inotropic response to angiotensin peptides, there is a dose-dependent increase in inositol-1-phosphate production in response to angiotensin II, and this response is blocked by the selective angiotensin II antagonist [Sar1,Ile8]angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Generation of inositol phosphates, cytosolic Ca2+, and secretion of noradrenaline in PC12 cells treated with glutamate.

Glutamate transiently stimulated rat pheochromocytoma PC12 cells and caused an inositol trisphosphate formation and an increase in levels of Ca+ in the cytosol. The rank order of potency of glutamate greater than N-methyl-D-aspartate (NMDA) much greater than kainate = quisqualate is characteristic of an interaction with NMDA receptors. The effect of glutamate on inositol trisphosphate formation disappeared in a low Mg2+ buffer and was not blocked by DL-2-amino-5-phosphonovalerate, an antagonist for NMDA receptors coupled to ion channels. Although glutamate failed to stimulate noradrenaline secretion, glutamate enhanced the effect of bradykinin, but not of Ca ionophore A23187, or KCl. These results suggest the existence of metabotropic glutamate receptors, different from previously reported receptors, in PC12 cells.

Adrenal Gland Neoplasms↗
PubMed1994

Calcium-dependence of histamine- and carbachol-induced inositol phosphate formation in human U373 MG astrocytoma cells: comparison with HeLa cells and brain slices.

1. Histamine (1 mM) induced an accumulation of inositol monophosphate ([3H]-IP1) in the U373 MG human astrocytoma cell line which increased with time in the presence of 30 mM Li+. After a 30 min incubation period with 1 mM histamine [3H]-IP1 was the major product detected (84 +/- 1% of total [3H]-IPx) and was present at a level 11 (+/- 1) fold of basal accumulation. 2. Concentration-response curves for histamine-induced [3H]-IP1 accumulation in U373 MG cells (EC50 5.4 +/- 0.5 microM) were shifted to the right in a parallel fashion by mepyramine (slope of a Schild plot 0.99 +/- 0.08), yielding a Kd for mepyramine of 3.5 +/- 0.3 nM, consistent with the involvement of histamine H1-receptors. 3. The temelastine-sensitive binding of [3H]-mepyramine to a membrane fraction from U373 MG cells was hyperbolic and had a mean Kd of 2.5 +/- 1.0 nM. The maximum amount of temelastine-sensitive binding was 86 +/- 19 pmol g-1 membrane protein. 4. Carbachol also induced [3H]-IP1 accumulation in U373 MG cells, 2.8 (+/- 0.1) fold of basal with 1 mM carbachol, with an EC50 of 48 +/- 8 microM. Pirenzepine shifted carbachol concentration-response curves to the right (slope of Schild plot 0.89 +/- 0.07) giving a Kd for pirenzepine of 0.10 +/- 0.01 microM, suggesting that phosphoinositide hydrolysis in U373 MG cells is mediated by the M3-, rather than the M1-, muscarinic receptor subtype. 5. [3H]-IP1 accumulation induced by both 1 mM histamine and by 1 mM carbachol increased when the Ca2+ concentration of the medium was increased from 'zero' (no added Ca2+) to 0.3 mM. Histamine-stimulated [3H]-IP1 accumulation was further increased, although not so markedly, as the Ca2+ was raised to 4 mM. The same pattern was apparent with histamine-induced accumulations of [3H]-IP2 and [3H]-IP3. In contrast, [3H]-IPx accumulation in response to carbachol increased between 0.3 and 1.3 mM, but thereafter remained unchanged ([3H]-IP1) or declined ([3H]-IP2 and [3H]-IP3). 6. In HeLa cells, [3H]-IP1 accumulations induced by 1 mM histamine and 1 mM carbachol showed the same pattern of Ca2+ dependence and were independent of extracellular Ca2+ above 0.3 mM (histamine) or 1.3 mM (carbachol). The response to carbachol appeared to be mediated by an M3-muscarinic receptor (apparent Kd for pirenzepine 0.09 microM). 7. In cross-chopped slices of guinea-pig cerebral cortex and guinea-pig cerebellum, [3H]-IPI accumulation induced by 1 mM histamine in the presence of 10 mM Li+ increased as the extracellular Ca2+ was increased from 0.3 to 2.5 mM, but a further increase to 4 mM had no further effect. In contrast the response to histamine in rat cerebral cortex increased markedly between 1.3 and 4 mM Ca2+. Accumulations of [3H]-IP1 induced by carbachol in guinea-pig or rat cerebral cortical slices were not increased as extracellular Ca2+ was raised from 0.3 to 4 mM.8. Nimodipine (100 nM) and w-conotoxin (3 microM) had no significant effect on histamine-induced [3H]-IP1accumulation in rat cerebral cortical slices or in U373 MG cells. 9. We conclude that histamine-induced [3H]-IP1 accumulation in U373 MG cells does appear to have a component dependent on the extracellular Ca2+ concentration. The degree of Ca2+-dependence approaches that observed in guinea-pig cerebral cortex but is much less than in rat cerebral cortex.Whether U373 MG cells will be of use as a model system for the apparent Ca2+-entry component observed in guinea-pig or rat brain slices remains to be established.

Animals↗
PubMed1989

Subcellular localization and kinetic properties of phosphatidylinositol 4,5-bisphosphate phospholipase C and inositol phosphate enzymes from human peripheral blood mononuclear cells.

Peripheral blood mononuclear cells from normal donors exhibited phosphatidylinositol 4,5-bisphosphate phospholipase C (PIP2-PLC), inositol 1,4,5-trisphosphate (IP3) and inositol 1-phosphate (IP)-monophosphatase activities which were mostly recovered in the cytosol fraction. In both cytosol and particulate fractions PIP2-PLC displayed the highest activity at pH 6.2, whereas IP3 and IP-monophosphatases showed the same optimal pH at 7.0. While the PIP2-PLC displayed close apparent Km values in cytosol and particulate fractions, both inositol-monophosphatases were found to show substrate affinities for IP and IP3 characteristic of these two fractions, with an higher affinity in the soluble fraction.

5'-Nucleotidase↗
PubMed1987

Binding of inositol phosphates and induction of Ca2+ release from pituitary microsomal fractions.

Bovine anterior-pituitary microsomal fractions exhibit high-affinity, saturable and reversible binding of inositol 1,4,5-[32P]trisphosphate; 50% of the labelled ligand is displaced by 3.5 nM-inositol 1,4,5-trisphosphate. 0.5 microM-inositol 1,4-bisphosphate and 10 microM-ATP. Inositol 1,4,5-trisphosphate induces the release of Ca2+ from the microsomal vesicles (half-maximal effect at 290 nM), and its action is potentiated by inositol tetrakisphosphate (half-maximal effect at 4 microM).

Animals↗
PubMed1994

Chronic L-alpha-glyceryl-phosphoryl-choline increases inositol phosphate formation in brain slices and neuronal cultures.

Repeated, but not single injections of L-alpha-glyceryl-phosphorylcholine (alpha GPC) significantly increased basal [3H]inositol monophosphate (InsP) formation in hippocampal, cortical, and striatal slices of male rats. The effect was dose-dependent and was accompanied by an increased incorporation of [3H]inositol into the phospholipid fraction. Incubation of brain slices with different neurotransmitter antagonists, such as atropine, prazosin, or L-2-amino-4-phosphonobutanoate (L-AP4) did not modify the increase in [3H]InsP formation produced by alpha GPC, suggesting that the effect is not mediated by an increased availability of a specific neurotransmitter. Similar results were obtained in cerebellar and cortico-striatal neurones in primary culture exposed to daily addition of alpha GPC since the second day of maturation in vitro. We suggest that alpha GPC treatment may result in an increased rate of phospholipid synthesis, including the phosphoinositides available for signal transduction at central nervous system level.

Animals↗
PubMed1989

Metabolism of inositol phosphates in alpha 1-adrenoceptor-stimulated and homogenized cardiac myocytes of adult rats.

Previous studies demonstrated the accumulation of inositol mono- and poly-phosphates in carbamoylcholine-stimulated cultured cardiac ventricular myocytes of adult rats [Berg, Guse & Gercken (1989) Biochim. Biophys. Acta 1010, 100-107]. Stimulation with noradrenaline (50 microM) in the presence of propranolol (10 microM) led to a time-dependent pattern of inositol mono- and poly-phosphates in cultured cardiac-ventricular myocytes. Ins(1,4,5)P3 and Ins(1,3,4,5)P4 increased in a rapid initial phase. The degradation products of Ins(1,4,5)P3, namely Ins(1,4)P2 and Ins(4)P, accumulated between 1 and 15 min. Ins(1,3,4,5)P4 was rapidly dephosphorylated to Ins(1,3,4)P3, which was then metabolized to Ins(1,3)P2 and Ins(3,4)P2. The last two InsP2 isomers and their degradation products, Ins(1)P and Ins(3)P (determined as an enantiomeric mixture), increased at extended stimulation periods. To confirm the pathway of Ins(1,3,4,5)P4 degradation, homogenates of isolated ventricular myocytes were incubated with [3H]INs(1,3,4,5)P4. The subsequent products were Ins(1,3,4)P3, Ins(3,4)P2, Ins(1,3)P2 and InsP. The effect of noradrenaline was antagonized by prazosin (0.1 microM), but not by yohimbine (0.1 microM), indicating phosphoinositidase activation via the alpha 1-adrenoceptor.

Animals↗
PubMed1988

Early events in inositol phosphate metabolism in longitudinal smooth muscle from guinea-pig intestine stimulated with carbachol.

In longitudinal smooth muscle from guinea-pig intestine prelabelled with [3H]inositol, carbachol produced a 3-fold increase in [3H]inositol 1,4,5-trisphosphate within 2 s, and there was also a simultaneous increase in [3H]inositol 1,4-bisphosphate. 3H-labelling of inositol 1,3,4,5-tetrakisphosphate was not significantly increased until 60 s after carbachol stimulation, and the accumulation of [3H]inositol 1,3,4-trisphosphate was relatively small.

Animals↗