scholarly journals myo-Inositol phosphorothioates, phosphatase-resistant analogues of myo-inositol phosphates. Synthesis of dl-myo-inositol 1,4-bisphosphate and dl-myo-inositol 1,4-bisphosphorothioate

1987 ◽  
Vol 246 (3) ◽  
pp. 771-774 ◽  
Author(s):  
M R Hamblin ◽  
J S Flora ◽  
B V L Potter
Keyword(s):  
Inositol Phosphates ◽  
Second Messenger ◽  
Inositol 1,4,5 Trisphosphate

Syntheses of a metabolite of the second messenger myo-inositol 1,4,5-trisphosphate, myo-inositol 1,4-bisphosphate, and an analogue, the 1,4-bisphosphorothioate, are reported, by using phosphite chemistry on (+/-)-1,2:4,5-di-isopropylidene-myo-inositol. The synthesis of (+/-)-1,2:4,5-di-isopropylidene 3,6-bis[di-(2-cyanoethyl)]phosphite provides an intermediate that can be oxidized to either the corresponding bisphosphate or bisphosphorothioate. myo-Inositol phosphorothioates are proposed as novel analogues of myo-inositol phosphates; their resistance to phosphatase-catalysed breakdown is reported.

scholarly journals Actions of inositol phosphates on Ca2+ pools in guinea-pig hepatocytes

1984 ◽  
Vol 224 (3) ◽  
pp. 741-746 ◽  
Author(s):  
G M Burgess ◽  
R F Irvine ◽  
M J Berridge ◽  
J S McKinney ◽  
J W Putney
Keyword(s):  
Endoplasmic Reticulum ◽  
Guinea Pig ◽  
Inositol Phosphates ◽  
Second Messenger ◽  
Release Mechanism ◽  
Specific Receptor ◽  
Rapid Release ◽  
Inositol 1,4,5 Trisphosphate

In permeabilized hepatocytes, inositol 1,4,5-trisphosphate, inositol 2,4,5-trisphosphate and inositol 4,5-bisphosphate induced rapid release of Ca2+ from an ATP-dependent, non-mitochondrial vesicular pool, probably endoplasmic reticulum. The order of potency was inositol 1,4,5-trisphosphate greater than inositol 2,4,5-trisphosphate greater than inositol 4,5-bisphosphate. The Ca2+-releasing action of inositol 1,4,5-trisphosphate is not inhibited by high [Ca2+], nor is it dependent on [ATP] in the range of 50 microM-1.5 mM. These results suggest a role for inositol 1,4,5-trisphosphate as a second messenger in hormone-induced Ca2+ mobilisation, and that a specific receptor is involved in the Ca2+-release mechanism.

scholarly journals Lithium stimulates accumulation of second-messenger inositol 1,4,5-trisphosphate and other inositol phosphates in mouse pancreatic minilobules without inositol supplementation

1994 ◽  
Vol 304 (1) ◽  
pp. 251-258 ◽  
Author(s):  
J F Dixon ◽  
L E Hokin
Keyword(s):  
Cerebral Cortex ◽  
Phospholipase C ◽  
Feedback Inhibition ◽  
Inositol Phosphates ◽  
Plasma Concentrations ◽  
Second Messenger ◽  
Inositol Polyphosphates ◽  
Peripheral Tissues ◽  
Inositol 1,4,5 Trisphosphate ◽  
Cortex Slices

Previous studies showed that lithium, beginning at therapeutic plasma concentrations in the treatment of manic depression, increased the accumulation of second-messenger inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in cerebral cortex slices of guinea pig and rhesus monkey [Lee, Dixon, Reichman, Moummi, Los and Hokin (1992) Biochem. J. 282, 377-385; Dixon, Lee, Los and Hokin (1992) J. Neurochem. 59, 2332-2335; Dixon, Los and Hokin (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 8358-8362]. These studies have now been extended to a peripheral tissue, mouse pancreatic minilobules. In the presence of carbachol, concentrations of lithium from 1 to 20 mM sharply and progressively increased the accumulation of Ins(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate, followed by a decrease. Assay of these inositol polyphosphates by either the prelabelling technique or mass assay gave similar results. Atropine quenching of cholinergically stimulated pancreatic minilobules led to a rapid disappearance of Ins(1,4,5)P3. This disappearance was impeded by lithium. This suggested that the lithium-induced elevation in Ins(1,4,5)P3 was due to inhibition of the 5-phosphatase and, on the basis of the markedly elevated concentrations of inositol 1,3,4-trisphosphate [Ins(1,3,4)P3] and inositol 1,4-bisphosphate in the presence of lithium, probably by feedback inhibition by these latter two compounds. An additional mechanism, i.e. a stimulatory effect of lithium on phospholipase C, cannot, however, be ruled out. The other reaction product of phospholipase C, inositol cyclic 1:2,4,5-trisphosphate, also increased in the presence of lithium. This may also be due to inhibition of the 5-phosphatase, which is the exclusive mechanism for removal of this compound. The effects of lithium on the accumulation of other inositol phosphates paralleled that of Ins(1,4,5)P3, with the exception of inositol 3,4-bisphosphate, which decreased. This was presumably due to the inhibition of Ins(1,3,4)P3 1-phosphatase by lithium. Unlike mouse cerebral cortex slices [Lee, Dixon, Reichman, Moummi, Los and Hokin (1992) Biochem. J. 282, 377-385], inositol supplementation was not required to demonstrate lithium-stimulated Ins(1,4,5)P3 accumulation in mouse pancreatic minilobules. This indicates that inositol depletion sufficient to impair lithium-stimulated Ins(1,4,5)P3 accumulation does not occur in mouse pancreatic minilobules, even though an elevation of cytidine diphosphodiacylglycerol occurred, indicating some inositol depletion due to lithium. Elevation of Ins(1,4,5)P3 by lithium may be a general phenomenon in the central nervous system and peripheral tissues under non-rate-limiting concentrations of inositol.

Selective permeability of different connexin channels to the second messenger inositol 1,4,5-trisphosphate

2000 ◽  
Vol 113 (8) ◽  
pp. 1365-1372 ◽  
Author(s):  
H. Niessen ◽  
H. Harz ◽  
P. Bedner ◽  
K. Kramer ◽  
K. Willecke
Keyword(s):  
Gap Junctions ◽  
Hela Cells ◽  
Second Messenger ◽  
Pancreatic Acinar Cells ◽  
Cell Coupling ◽  
Liver Parenchymal ◽  
Fura 2 ◽  
Inositol 1,4,5 Trisphosphate ◽  
Messenger Molecules ◽  
Parenchymal Cells

Intercellular propagation of signals through connexin32-containing gap junctions is of major importance in physiological processes like nerve activity-dependent glucose mobilization in liver parenchymal cells and enzyme secretion from pancreatic acinar cells. In these cells, as in other organs, more than one type of connexin is expressed. We hypothesized that different permeabilities towards second messenger molecules could be one of the reasons for connexin diversity. In order to investigate this, we analyzed transmission of inositol 1,4,5-trisphosphate-mediated calcium waves in FURA-2-loaded monolayers of human HeLa cells expressing murine connexin26, -32 or -43. Gap junction-mediated cell coupling in different connexin-transfected HeLa cells was standardized by measuring the spreading of microinjected Mn(2+) that led to local quenching of FURA-2 fluorescence. Microinjection of inositol 1,4,5-trisphosphate into confluently growing HeLa connexin32 transfectants induced propagation of a Ca(2+) wave from the injected cell to neighboring cells that was at least three- to fourfold more efficient than in HeLa Cx26 cells and about 2.5-fold more efficient than in HeLa Cx43 transfectants. Our results support the notion that diffusion of inositol 1,4,5-trisphosphate through connexin32-containing gap junctions is essential for the optimal physiological response, for example by recruiting liver parenchymal cells that contain subthreshold levels of this short lived second messenger.

scholarly journals Formation of methylphosphoryl inositol phosphates by extractions that employ methanol

1988 ◽  
Vol 253 (3) ◽  
pp. 703-710 ◽  
Author(s):  
J E Brown ◽  
M Rudnick ◽  
A J Letcher ◽  
R F Irvine
Keyword(s):  
Alkaline Phosphatase ◽  
Methanol Extract ◽  
Inositol Phosphates ◽  
Red Cell ◽  
Unknown Compound ◽  
Methyl Group ◽  
Phosphatidylinositol Bisphosphate ◽  
Inositol 1,4,5 Trisphosphate ◽  
Inositol Ring ◽  
Retinal Volume

Fixatives that contain methanol extract an unknown compound from several tissues including the retinas of squid (Loligo). We have determined that the compound probably contains (1) a myo-inositol ring that is phosphorylated in more than one position (including at the 5-hydroxyl), (2) a charged moiety that is not susceptible to alkaline phosphatase, and (3) a methyl group. We have found that the compound can be made by treating either phosphatidylinositol bisphosphate or human red cell ghosts with acidic methanol. We have confirmed the observation of Lips, Bross & Majerus [Proc. Natl. Acad. Sci. U.S.A. 85, 88-92] that the compound also can be made by methanolysis of inositol (cyclic 1:2,4,5)trisphosphate; however, we have not found inositol (cyclic 1:2,4,5)trisphosphate in either stimulated or unstimulated squid retinas. We tentatively identify the compound as (1-methylphosphoryl)inositol 4,5-bisphosphate formed by methanolysis of phosphatidylinositol 4,5-bisphosphate. By using this methanolysis to incorporate label from [14C]methanol, we have estimated the mass of inositol 1,4,5-trisphosphate in squid retinas to be approx. 30 mumol/l of retinal volume.

scholarly journals Separation of multiple isomers of inositol phosphates formed in GH3 cells

1987 ◽  
Vol 242 (2) ◽  
pp. 361-366 ◽  
Author(s):  
N M Dean ◽  
J D Moyer
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
High Performance ◽  
Inositol Phosphates ◽  
Thyrotropin Releasing Hormone ◽  
Gh3 Cells ◽  
Releasing Hormone ◽  
Inositol 1 ◽  
Trh Stimulation ◽  
Inositol 1,4,5 Trisphosphate

A high-performance-liquid-chromatography (h.p.l.c.) separation was developed, which resolves isomers of inositol monophosphate (IP), inositol bisphosphate (IP2), and inositol trisphosphate (IP3) in a single run. In GH3 cells labelled with [3H]inositol, treated with Li+ and thyrotropin-releasing hormone (TRH), radiolabelled components identified as inositol 1-phosphate (I1P), inositol 2-phosphate (I2P), inositol 4-phosphate (I4P), inositol 1,4-bisphosphate [I(1,4)P2], inositol 1,3,4-trisphosphate [I(1,3,4)P3] and inositol 1,4,5-trisphosphate [I(1,4,5)P3] are present, as are multiple unidentified IP2 peaks. After TRH stimulation, both I1P and I4P increase, the increase in I4P preceding that of I1P; I(1,4)P2 and an unknown IP2 increase; and both I(1,3,4)P3 and I(1,4,5)P3 increase, the increase in I(1,4,5)P3 being rapid and transient, whereas the increase in I(1,3,4)P3 is slower and more sustained. The most rapidly appearing inositol phosphates produced after TRH stimulation are I(1,4)P2 and I(1,4,5)P3.

scholarly journals Relationships between the degree of cross-linking of surface immunoglobulin and the associated inositol 1,4,5-trisphosphate and Ca2+ signals in human B cells

1992 ◽  
Vol 284 (2) ◽  
pp. 447-455 ◽  
Author(s):  
F M McConnell ◽  
S B Shears ◽  
P J L Lane ◽  
M S Scheibel ◽  
E A Clark
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
Phospholipase C ◽  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Cross Linking ◽  
Immunoglobulin Receptor ◽  
Surface Immunoglobulin ◽  
Human B Cells ◽  
Inositol 1,4,5 Trisphosphate

Cross-linking of surface immunoglobulin (Ig) receptors on human B cells leads to the activation of a tyrosine kinase. The activated tyrosine kinase subsequently phosphorylates a number of substrates, including phospholipase C-gamma. This enzyme breaks down phosphoinositol bisphosphate to form two intracellular messengers, diacylglycerol and inositol 1,4,5-trisphosphate, leading to the activation of protein kinase C and the release of intracellular Ca2+ respectively. We have used h.p.l.c. and flow cytometry to measure accurately the inositol phosphate turnover and Ca2+ release in anti-Ig-stimulated human B cells. In particular, we have examined the effect of dose of the cross-linking antibody on the two responses. The identity of putative messenger inositol phosphates has been verified by structural analysis, and the amounts of both inositol phosphates and Ca2+ present have been quantified. In the Ramos Burkitt lymphoma, which is very sensitive to stimulus through its Ig receptors, both inositol phosphate production and Ca2+ release were found to be related to the dose of anti-Ig antibody applied. This suggests that phospholipase C-mediated signal transduction in human B cells converts the degree of cross-linking of the immunoglobulin receptor quantitatively into intracellular signals.

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