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W R Sherman

Publications and source records attributed to W R Sherman.

At least 55 records · Page 3Linked to original sources
PubMed1986

Effects of lithium on phosphoinositide metabolism in vivo.

All of the known pathways for metabolizing the phospholipase C (EC 3.1.4.10) products of phosphoinositide metabolism eventually lead to myo-inositol monophosphates and products that are hydrolyzed by myo-inositol 1-phosphatase (EC 3.1.3.25). That enzyme is inhibited by lithium (Ki about 1 mM). In animals treated with LiCl, elevations of myo-inositol 1-phosphate (1-IP) occur in brain that appear to result from endogenous neural activity for they are diminished by the anesthetics halothane and pentobarbital. Lithium is thus a useful tool for assessing endogenous in vivo cerebral phosphoinositide metabolism. The 1-IP elevation is also useful for revealing in vivo central nervous system (CNS) receptor activity that is stimulated by endogenous or exogenous processes such as the effects of centrally acting drugs and of seizures. Stimulation of the CNS in the presence of lithium causes myo-inositol to be sequestered in 1-IP in proportion to the amount of stimulation. Thus if the inositol level falls sufficiently resynthesis of the phosphoinositides may be compromised and receptor response to stimuli may be reduced. Evidence for such an occurrence would support the theory that this is one mechanism by which lithium acts in the therapy of manic illness. We extended our efforts to identify such a lowering of phosphoinositide levels to mice where cerebral metabolism can be halted more rapidly than in rats. However, the only change detected was a small elevation in phosphatidylinositol 4-phosphate. We were successful, however, in causing all of the phosphoinositides to be reduced in rat cerebral cortex by pilocarpine stimulation after lithium treatment, a procedure that causes seizures. The same procedure causes the largest reduction in cortical myo-inositol levels that we have observed, and thus may represent the point where the inositol decrement is sufficient to interfere with resynthesis of the lipids.

Animals↗
PubMed1985

Isolation and characterization of the inositol cyclic phosphate products of polyphosphoinositide cleavage by phospholipase C. Physiological effects in permeabilized platelets and Limulus photoreceptor cells.

Cleavage of the polyphosphoinositides, catalyzed by phospholipase C purified from ram seminal vesicles, produces phosphorylated inositols containing cyclic phosphate esters (Wilson, D. B., Bross, T. E., Sherman, W. R., Berger, R. A., and Majerus, P. W. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 4013-4017). In the present study we describe the isolation and characterization of inositol 1:2-cyclic 4-bisphosphate and inositol 1:2-cyclic 4,5-trisphosphate, the two cyclic phosphate products of phospholipase C catalyzed cleavage of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate, respectively. We established the structures of these two cyclic compounds through 18O labeling of phosphate moieties, phosphomonoesterase digestion, and fast atom bombardment-mass spectrometry. We examined the physiological effects of these compounds in two systems: saponin-permeabilized platelets loaded with 45Ca2+ and intact Limulus photoreceptors. Both inositol 1:2-cyclic 4,5-trisphosphate and the noncyclic inositol 1,4,5-trisphosphate, but not inositol 1:2-cyclic 4-bisphosphate, release 45Ca2+ from permeabilized platelets in a concentration-dependent manner. Injection of inositol 1:2-cyclic 4,5-trisphosphate into Limulus ventral photoreceptor cells induces both a change in membrane conductance and a transient increase in intracellular calcium ion concentration similar to those induced by light. We injected inositol 1,4,5-trisphosphate and inositol 1:2-cyclic 4,5-trisphosphate into the same photoreceptor cell and found that the cyclic compound is approximately five times more potent than the noncyclic compound in stimulating a conductance change. We speculate that inositol 1:2-cyclic 4,5-trisphosphate may function as a second messenger in stimulated cells.

Animals↗
PubMed1985

Anomeric and other substrate specificity studies with myo-inositol-1-P synthase.

L-myo-Inositol-1-phosphate synthase has been found to have at least a 5-fold preference for the beta-anomer of its natural substrate D-Glc-6-P. The alpha-anomer appears to be an inhibitor of the reaction and may be converted to product as well. As well as showing an enzymatic preference for the equatorial C-1 hydroxyl of D-Glc-6-P, our results suggest that it is the pyranose form of D-Glc-6-P that binds to the enzyme and that ring-opening is an enzymatic step. We have also found D-2-dGlc-6-P, D-2-F-2-dGlc-6-P, and D-Man-6-P each to be both competitive inhibitors and substrates that are converted to inositol phosphates by the synthase. D-Allose-6-P is a weak inhibitor of the enzyme, but not a substrate. D-Gal-6-P is neither substrate nor inhibitor. Thus the specificity of the synthase with respect to single position epimers of D-Glc-6-P increases in the order C1 less than C2 much less than C3 less than C4.

Animals↗
PubMed1985

Monitoring the time course of cerebral deoxyglucose metabolism by 31P nuclear magnetic resonance spectroscopy.

The phosphorylation of 2-deoxyglucose by the mammalian brain is used as an index of the brain's energy metabolism. The results of phosphorus-31 nuclear magnetic resonance (31P NMR) monitoring of conscious animals in vivo showed rapid phosphorylation of 2-deoxyglucose by brain tissue. The rate of phosphorylation as determined by 31P NMR was consistent with results achieved by tracer methods using carbon-14-labeled 2-deoxyglucose. However, the disappearance of 2-deoxyglucose-6-phosphate was shown to be faster than that reported by tracer studies and occurred without alterations of intracellular pH and energy homeostasis. These results were confirmed by gas chromatography and mass spectroscopy. It is postulated that 2-deoxyglucose may be metabolized in several ways, including dephosphorylation by a hexose phosphatase.

Animals↗
PubMed1985

Identification of covalently bound inositol in the hydrophobic membrane-anchoring domain of Torpedo acetylcholinesterase.

The hydrophobic, membrane-bound form of Torpedo acetylcholinesterase is specifically solubilized by a phosphatidylinositol-specific phospholipase C, suggesting that acetylcholinesterase is bound to the membrane via a direct and specific interaction with phosphatidylinositol (Futerman et al., Biochem. J. (1985) 226, 369-377). Here we demonstrate the presence of covalently bound inositol in the membrane-anchoring domain of purified Torpedo acetylcholinesterase. Upon removal of this domain, levels of inositol are reduced to only 15-20% of those found in the intact enzyme. The results presented strongly support our suggestion that phosphatidylinositol is indeed involved in anchoring acetylcholinesterase to the plasma membrane.

Acetylcholinesterase↗
PubMed1985

The digitonin-permeabilized pancreatic islet model. Effect of myo-inositol 1,4,5-trisphosphate on Ca2+ mobilization.

Glucose-induced insulin secretion is thought to be mediated by submicromolar increases in intracellular Ca2+, although the intracellular processes are not well understood. We have used the previously characterized digitonin-permeabilized insulin-secreting pancreatic islet model to study the role of myo-inositol 1,4,5-trisphosphate (IP3), a putative second messenger for mobilization of intracellular Ca2+. Ca2+ efflux from the endoplasmic reticulum was studied with or without vanadate present to inhibit Ca2+ reuptake. IP3 (10 microM), at a free Ca2+ level of 0.06 microM, increased Ca2+ release by 30% and, when vanadate was present, by 50%. Maximal and half-maximal Ca2+ release was observed at 10 microM- and 2.5 microM-IP3, respectively. IP3 provoked a rapid release that was followed by slow reuptake. Reuptake was diminished in the presence of vanadate. Inositol 1,4-bisphosphate, inositol 1-phosphate and other phosphoinositide metabolites did not have any significant effect. Because increases in Ca2+ levels in the submicromolar range have been previously shown to induce insulin release in digitonin-permeabilized islets, our results are consistent with the concept of IP3 serving as a second messenger for insulin secretion.

Adenosine Triphosphate↗
PubMed1985

Mass-analysed ion kinetic energy spectra and B1E-B2 triple sector mass spectrometric analysis of phosphoinositides by fast atom bombardment.

Fast atom bombardment is shown to produce useful spectra of the three phosphoinositides and the metabolically related phospholipids, lysophosphatidylinositol and phosphatidic acid. Analysis of the [M-H]- ions for fatty ester composition by mass-analysed ion kinetic energy spectra (MIKES) is shown to be inadequate to resolve fatty acyl daughter ions when the parent ion contains isobaric species. However, analysis on a triple sector instrument with and without collisional activation does provide complete compositional information. Quantitative analysis of the fatty ester content of each lipid molecular species is complicated by dissimilar ion yields from fatty acyl-bearing fragments from compositionally different parent ions.

Animals↗
PubMed1985

Inositol cyclic phosphates are produced by cleavage of phosphatidylphosphoinositols (polyphosphoinositides) with purified sheep seminal vesicle phospholipase C enzymes.

Previous studies have shown that metabolism of phosphatidylinositol by phospholipase C produces a mixture of two water-soluble products: inositol 1-phosphate and inositol 1,2-(cyclic)phosphate. In the present study, we demonstrate that the water-soluble products of phosphatidylphosphoinositol (polyphosphoinositide) cleavage by purified ram seminal vesicle phospholipase C enzymes also contain cyclic phosphates. Inositol cyclic phosphates were detected by 18O labeling. In the presence of acid, cyclic phosphates are rapidly hydrolyzed to phosphomonoesters, and when the hydrolysis is carried out in H2 18O, the resultant phosphomonoesters will contain 18O. The 18O content of the phosphomonoesters was measured following alkaline phosphatase treatment and conversion of the inorganic phosphate to a volatile derivative for gas chromatography/mass spectrometry. Inositol cyclic phosphates were found in the phospholipase C cleavage products of all three phosphoinositides, but the ratio of cyclic to noncyclic product was found to decrease in the order phosphatidylinositol greater than phosphatidylinositol 4-phosphate greater than phosphatidylinositol 4,5-bisphosphate. The formation of myo-inositol 1,2(cyclic)-4-bisphosphate was further substantiated by anion-exchange HPLC of the water-soluble products of [32P]phosphatidylinositol 4-phosphate metabolism by phospholipase C. Two peaks were detected one of which, on acid treatment, incorporated 18O from H2 18O into phosphate groups, consistent with this peak containing the cyclic phosphate product. These results suggest that polyphosphoinositide breakdown in stimulated cells may occur via a cyclic phosphate intermediate, as has been described for phosphatidylinositol. These cyclic phosphates contain a reactive bond that may play a role in phosphoinositide-derived signal transduction.

Animals↗
PubMed1985

Effects of systemically administered lithium on phosphoinositide metabolism in rat brain, kidney, and testis.

A single subcutaneous dose of 10 mEq/kg LiCl gives rise to an increase in the cerebral cortex level of myo-inositol-1-P (I1P) that closely follows cortical lithium levels and, at maximum, is 40-fold above the control value. Kidney and testis show smaller increases in I1P level following LiCl administration. The I1P level is still sixfold greater than that of untreated rat cortex 72 h later. In cortex, parallel increases also occur in myo-inositol-4-P (I4P) and myo-inositol 1,2-cyclic-P (cI1,2P), whereas myo-inositol-5-P (I5P) remains unchanged. The cortical increases in I1P and I4P levels are partially reversed by administering 150 mg/kg of atropine 22 h after the LiCl, treatment that does not affect cI1,2P. When doses of LiCl from 2 to 17 mEq/kg are given, the cerebral cortex levels of I1P and myo-inositol, measured 24 h later, are found to reach a plateau at about 9 mEq/kg of LiCl, whereas cortical lithium levels continued to increase with greater LiCl doses. Levels of all three of the brain phosphoinositides are unchanged by the 10 mEq/kg LiCl dose, as is the uptake of 32Pi into these lipids. Chronic dietary administration of LiCl for 22 days showed that the effects of lithium on I1P and myo-inositol levels persist for that period. Over the course of the chronic administration of the lithium, levels of I1P, myo-inositol, and of lithium in cortex remained significantly correlated. We believe that these increases in inositol phosphates result from endogenous phosphoinositide metabolism in cerebral cortex and that lithium is capable of modulating that metabolism by reducing cellular myo-inositol levels. The size of the effect is a function of both lithium dose and the degree of stimulation of receptor-linked phosphoinositide metabolism. This property of lithium may explain part of its ability to moderate the symptoms of mania. Our chronic study suggests that prolonged administration of LiCl does not result in compensatory changes in myo-inositol-1-P synthase or myo-inositol-1-phosphatase.

Administration, Oral↗
PubMed1985

Sorbinil prevents diabetes-induced increases in vascular permeability but does not alter collagen cross-linking.

In recent studies we have demonstrated a marked increase in albumin permeation of new vessels formed by angiogenesis (in subcutaneous tissue) in the diabetic milieu. Likewise, lysyl oxidase-mediated collagen cross-linking is markedly increased in the scar tissue associated with angiogenesis. The present studies were undertaken to determine whether sorbinil, a chemical inhibitor of aldose reductase that has been shown to prevent and reverse diabetic cataracts and neuropathy, also could prevent the vascular permeability and collagen cross-linking changes in this model. Vascular permeation by 125I-BSA, collagen cross-linking, and tissue levels of sorbitol, myo-inositol, and scyllo-inositol were assessed in male Sprague-Dawley rats 3 wk after injection of streptozocin and induction of angiogenesis and collagen synthesis in polyester fabric implanted subcutaneously. Sorbinil (approximately 25 mg/kg/day) added to the diet of diabetic rats reduced the diabetes-induced increases in albumin permeation by 80%, completely prevented diabetes-induced changes in tissue levels of sorbitol and myo-inositol, and markedly reduced diabetes-induced changes in tissue levels of scyllo-inositol. In contrast, sorbinil had no effect on plasma glucose levels or collagen solubility (an index of collagen cross-linking). These observations indicate that increased vascular permeability associated with diabetes is linked to imbalances in sorbitol/inositol metabolism. These findings also indicate that diabetes-induced increases in vascular permeability and in collagen cross-linking are independent phenomena and diabetes-induced increases in vascular permeability are largely preventable by treatment with an aldose reductase inhibitor in the face of high plasma glucose levels.

Albumins↗
PubMed1984

Differential uptake of lithium isotopes by rat cerebral cortex and its effect on inositol phosphate metabolism.

Twenty hours following the subcutaneous administration of 5 mEq/kg doses of 6LiCl and 7LiCl to two groups of rats, the cerebral cortex molar ratio of 6Li+/7Li+ is 1.5. The effects of the lithium isotopes on cortex myo-inositol and myo-inositol-l-phosphate levels are the same as we have reported earlier: a Li+ concentration-dependent lowering of myo-inositol and increase in myo-inositol-1-phosphate. Thus 6LiCl, when administered at the same dose as 7LiCl, produces the larger effect on inositol metabolism. When the 6LiCl and 7LiCl doses were adjusted to 5 mEq/kg and 7 mEq/kg, respectively, the cortical lithium myo-inositol and myo-inositol-1-phosphate levels of each group of animals became approximately equal, suggesting that the isotope effect occurs at the level of tissue uptake, but not on inositol phosphate metabolism. The inhibition of myo-inositol-1-phosphatase by the two lithium isotopes in vitro showed no differential effect. The isotope effect on cerebral cortex uptake of lithium is in the same direction as that reported by others for erythrocytes and for the CSF/plasma ratio, but of larger magnitude.

Animals↗
PubMed1983

Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats.

Administration of pilocarpine or physostigmine to rats treated with lithium chloride produced sustained limbic seizures, widespread brain damage, and increased concentrations of D-myo-inositol-1-phosphate (a metabolite of the phosphoinositides, lipids involved in membrane receptor function) in the brain. The syndrome was preventable with atropine. The physostigmine doses and concentrations of blood lithium that caused the syndrome are similar to those considered appropriate for psychiatric chemotherapy.

Animals↗
PubMed1982

Enantiomeric Form of myo-Inositol-1-Phosphate Produced by myo-Inositol-1-Phosphate Synthase and myo-Inositol Kinase in Higher Plants.

The product of myo-inositol-1-phosphate synthase, EC 5.5.1.4, from mature pollen of Lilium longiflorum Thunb., cv Ace (Easter lily) and that of myo-inositol kinase, EC 2.7.1.64, from wheat germ has been identified as 1l-myo-inositol-1-phosphate by gas chromatography of its trimethylsilyl-methyl phosphate derivative on a glass capillary column bearing a chiral phase.

Journal Article↗
PubMed1982

Distribution of myo-inositol in the cat cochlear nucleus.

The distribution of myo-inositol, a substance that has been implicated in synaptic transmission, has been mapped within sections of the cat cochlear nucleus as well as some nearby regions. Highest values in the cochlear nucleus were found in regions of granule cells along the periphery of the anteroventral subdivision of the nucleus. Highest values overall were found in the molecular layer of the cerebellar flocculus. A fairly good correlation was found between myo-inositol levels and activities of the enzymes of acetylcholine metabolism in the cat cochlear nucleus, supporting the possibility that myo-inositol may be involved in cholinergic synaptic transmission. No positive correlation was found between myo-inositol levels and the levels of glutamate, aspartate, glycine, or gamma-aminobutyric acid (GABA). The most striking gradient of myo-inositol levels within a region was found in the auditory nerve, where different myo-inositol levels might be related to nerve fibers innervating different parts of the cochlea. The distribution of scyllo-inositol, a stereoisomer of myo-inositol, was also examined, and found to parallel closely the distribution of myo-inositol, with levels 4--5% as high.

Acetylcholinesterase↗
PubMed1981

Synthesis of sedoheptulose from non-dialyzable, endogenous substrates in mammalian tissue extracts.

Sedoheptulose was observed to be formed at the rate of 12-120 nmol/g tissue/h in dialyzed rat and bovine tissue homogenates. The compound was identified by its gas-chromatographic retention time and by its mass spectrum. A standard of [14C]-sedoheptulose was prepared from D-[14C]fructose 6-phosphate and D-erythrose 4-phosphate for use in radioactive gas-chromatographic analysis in studies of possible precursors of the sedoheptulose. The reaction was stimulated by NAD+. Evidence is presented to show that non-dialyzable sedoheptulose 7-phosphate may be the endogenous precursor. These results show that care must be exercised when using crude enzyme preparations and extremely sensitive analytical methods so that chromatographically unresolved products formed from non-dialyzable, endogenous substrates of low molecular weight do not introduce significant error in the analysis of the expected product.

Animals↗