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PubMed1997

Actions of C-type natriuretic peptide and sodium nitroprusside on carbachol-stimulated inositol phosphate formation and contraction in ciliary and iris sphincter smooth muscles.

PURPOSE: To investigate the effects of C-type natriuretic peptide (CNP) and sodium nitroprusside (SNP) on cyclic guanosine monophosphate (cGMP) accumulation and on carbachol (CCh)-stimulated inositol 1,4,5-triphosphate (IP3) production and contraction in ciliary muscle (CM) and iris sphincter (Sph) isolated from bovine and other mammalian species. METHODS: Ciliary muscle and sphincter isolated from cows, cats, dogs, rabbits, monkeys, and humans were used. Bovine specimens were used in the present work. Accumulation of cGMP and cyclic adenosine monophosphate (cAMP) in tissue extracts was measured by radioimmunoassay, IP3 production was measured by ion-exchange chromatography, and changes in tension were recorded isometrically. RESULTS: In general, CNP and SNP exerted differential inhibitory effects on muscarinic-receptor-induced responses in CM and Sph isolated from the various species. Thus in bovine CM, SNP stimulated cGMP formation in a time- and concentration-dependent manner and dose dependently inhibited CCh-induced IP3 production and contraction. These effects were inhibited by LY 83583, a soluble guanylyl cyclase inhibitor, and mimicked by 8-Br-cGMP, a cell-membrane permeable analogue of cGMP. The inhibitory effects of the soluble cGMP analogue are tissue and species specific. Sodium nitroprusside had no effect on the muscarinic responses in bovine Sph, but it attenuated CCh-induced contractions in Sph isolated from cats, dogs, and rabbits. In bovine Sph, CNP increased cGMP accumulation in a time- and dose-dependent manner and dose dependently inhibited CCh-induced IP3 production and contraction. LY 83583 had no effect on the muscarinic responses. C-type natriuretic peptide attenuated CCh-induced contraction in CM isolated from monkey and human, but it had no influence on this response in CM isolated from cows, cats, and dogs. CONCLUSIONS: In bovine CM, SNP effects are probably mediated through soluble guanylyl cyclase, whereas in Sph the CNP effects are mediated through membrane-bound guanylyl cyclase, which is associated with the type-B natriuretic peptide receptor. Agents that strongly increase intracellular cGMP levels, including SNP and CNP, produce significant inhibition of CCh-induced IP3 production and contraction. These effects are tissue and species specific. The results indicate that the cGMP signaling system, similar to the cAMP system, has a major inhibitory influence on the muscarinic responses in smooth muscles of the iris-ciliary body. The agents CNP and SNP, which stimulate cGMP accumulation in the ocular smooth muscles, could reduce intraocular pressure, presumably by increasing uveoscleral outflow induced by relaxation of the CM. However, the relationships between the CNP- and SNP-induced inhibition of the muscarinic stimulation and the reported intraocular pressure-lowering effects of the cGMP-elevating agents remain to be determined.

Aminoquinolines↗
PubMed1985

Pertussis toxin inhibits chemotactic peptide-stimulated generation of inositol phosphates and lysosomal enzyme secretion in human leukemic (HL-60) cells.

The binding of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine to its cell surface receptor rapidly elicits the hydrolysis of phosphatidylinositol 4,5-bisphosphate by phospholipase C to form the putative second messengers inositol 1,4,5-trisphosphate and sn-1,2-diacylglycerol. To investigate the possible role of a guanine nucleotide binding protein in transduction of this membrane signal, we examined the effects of pertussis toxin on chemotactic peptide-stimulated inositol phospholipid metabolism in differentiated HL-60 cells labeled with [3H]inositol. Pertussis toxin inhibited the chemotactic tripeptide-stimulated production of inositol mono-, bis-, and trisphosphates and secretion of N-acetyl-beta-D-glucosaminidase in a time- and concentration-dependent manner. Treatment with pertussis toxin did not alter the total incorporation or the distribution of [3H]inositol in inositol phospholipid. Chemotactic peptide receptor number was unchanged, although a slight decrease in binding affinity was observed. These findings suggest a role for a guanine nucleotide binding protein in coupling the chemotactic peptide receptor to phospholipase C.

Animals↗
PubMed1990

Oxytocin-stimulated inositol phosphate turnover in endometrium of ewes is influenced by stage of the estrous cycle, pregnancy, and intrauterine infusion of ovine conceptus secretory proteins.

Three experiments (Exp) assessed the influence of stage of the estrous cycle, pregnancy, and intrauterine infusion of ovine conceptus secretory proteins (oCSP) on turnover of inositol trisphosphate (the putative second-messenger for oxytocin-stimulated secretion of prostaglandin F2 alpha) in ovine endometrium during luteolysis and maternal recognition of pregnancy. In Exp 1, endometrium was collected from 5 cyclic (Cy) and 6 pregnant (P) ewes on Day 16 after onset of estrus. In Exp 2, endometrium was collected from Day 12 Cy (n = 5), Day 12 P (n = 3), Day 16 Cy (n = 4), and Day 16 P (n = 3) ewes. In Exp 3, 12 Cy ewes were allotted randomly, in a 2 x 2 factorial arrangement, to receive serum protein (SP), or oCSP and estradiol-17 beta (E2), or vehicle treatments. Ewes were injected i.v. with 0.5 mg E2 or vehicle on Day 12 and received twice-daily infusions of 1.5 mg SP or oCSP (containing 25 micrograms ovine trophoblast protein-1 by radioimmunoassay [RIA]) + SP (1.5 mg total protein) into each uterine horn on Days 12, 13, and 14. Blood samples for RIA of plasma progesterone were collected on Days 10-15 (before treatment on each day) and endometrium was collected on Day 15. For each Exp, 100 mg endometrium was incubated, in duplicate, for 2 h with 10 microCi [3H] inositol and treated with 0 or 100 nM oxytocin (OT) for 20 min, then [3H]inositol mono-, bis-, and trisphosphates (IP1, IP2, and IP3, respectively) were quantified.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Inositol-phosphate response to oxytocin stimulation in dispersed bovine mammary cells.

The effect of oxytocin on the breakdown of phosphoinositides in dispersed bovine mammary cells was studied. In the presence of 10 mM LiCl, addition of oxytocin to dispersed bovine mammary cells in which phosphatidylinositol was pre-labelled caused a time and dose-dependent increase in radioactive inositol monophosphate incorporation. These results suggested that the breakdown of phosphoinositides may be the linkage between the oxytocin receptor and contraction of mammary myoepithelial cells.

Animals↗
PubMed1993

[Ca2+]i-sensitive, IP3-independent Ca2+ influx in smooth muscle of rat vas deferens revealed by procaine.

1. The actions of procaine (10 mM) on noradrenaline-induced effects on 45Ca-influx, 45Ca-efflux, 45Ca-content, total inositol phosphates, inositol-1,4,5-trisphosphate, and contractile status of the rat was deferens were examined. 2. Noradrenaline alone had no effect on 45Ca-influx or 45Ca-content, but released Ca2+ from intracellular stores as indicated by an increased 45Ca-efflux and increased total inositol phosphates, specifically inositol-1,4,5-trisphosphate, leading to contraction of the rat vas deferens. 3. Noradrenaline, in the presence of 10 mM procaine, increased 45Ca-influx and 45Ca-content. Procaine blocked the noradrenaline-induced 45Ca-efflux, the increase in total inositol phosphates, the increase in inositol-1,4,5-trisphosphate, and contraction. 4. The noradrenaline-induced increase in 45Ca influx which was observed in the presence of procaine was abolished by phentolamine and nifedipine but was not altered significantly by propranolol suggesting that, in the presence of procaine, noradrenaline activates dihydropyridine-sensitive calcium channels through alpha-adrenoceptors. 5. These findings indicate that, in the rat vas deferens, noradrenaline induces contraction by releasing intracellularly stored Ca2+. The effects of procaine appear to be due to its ability to block the release of Ca2+ from intracellular stores. Furthermore, the simultaneous increase in 45Ca influx and inhibition of inositol-1,4,5-trisphosphate formation in tissues treated with procaine plus noradrenaline indicates that Ca2+ influx is independent of inositol-1,4,5-trisphosphate formation.

Animals↗
PubMed1992

Hepatocyte growth factor induces calcium mobilization and inositol phosphate production in rat hepatocytes.

The effects of hepatocyte growth factor (HGF) on intracellular Ca2+ mobilization were studied using fura-2-loaded single rat hepatocytes. Hepatocytes microperfused with different amounts of HGF responded with a rapid concentration-dependent rise in the cytosolic free Ca2+ concentration with a maximum increase of 142% at 80 ng/ml of HGF. The lag period of the Ca2+ response was decreased with increasing HGF concentrations, being 64 +/- 12 s, 42 +/- 6 s, and 14 +/- 2 s, respectively, with 8, 20, and 80 ng/ml of HGF. The detailed pattern of Ca2+ transients, however, was variable. Out of 16 cells tested using 20 ng/ml of HGF, 68% showed sustained oscillatory responses, whereas other cells showed a sustained increase in the cytosolic-free Ca2+ upon exposure to HGF, which was dependent on the presence of extracellular Ca2+. HGF also induced Ca2+ entry across the plasma membrane. Mobilization of Ca2+ by HGF was accompanied by a rapid accumulation of inositol 1,4,5-trisphosphate (Ins 1,4,5-P3). The effects of HGF and epidermal growth factor (EGF) were comparable and partly additive for Ins 1,4,5-P3 production and for the sustained phase of Ca2+ mobilization. Preincubation of cells with 10 microM of genistein to inhibit protein tyrosine kinases abolished the HGF-induced Ca2+ response and also inhibited HGF-induced Ins 1,4,5-P3 production in rat liver cells. These data indicate that early events in the signal transduction pathways mediated by HGF and EGF have in common the requirements for tyrosine kinase activity, Ins 1,4,5-P3 production, and Ca2+ mobilization.

Animals↗
PubMed1987

Breakdown of phosphoinositides in airway smooth muscle: lack of influence of anti-asthmatic drugs.

Hydrolysis of membrane inositol phospholipids during agonist-induced contraction in bronchial smooth muscle leads to formation of inositol phosphates. Inositol phosphates are associated with intracellular Ca++ mobilization, which in smooth muscle leads to contraction. We have investigated the effects of inhibitors of the contraction, theophylline, isoproterenol (isoprenaline), and verapamil, on contraction due to carbachol and histamine in bovine airway smooth muscle, and on the formation of inositol phosphates in the same preparation. Since phospholipase C and A2 are involved in the formation of inositol phosphates, we have also studied the effect of inhibitors of phospholipases, dexamethasone and mepacrine, on the accumulation of inositol phosphates. Theophylline, isoproterenol and verapamil elicited a concentration-dependent relaxation of pre-contracted smooth muscle, with the following order of potency: Isoproterenol greater than verapamil greater than theophylline. The relaxant effect was more effective on histamine than on carbachol-induced contraction and depended on the initial airway tone. However, neither theophylline, isoproterenol or verapamil, nor dexamethasone or mepacrine changed the basal level of inositol phosphates or affected the rise due to agonists. We conclude that the smooth muscle effects of theophylline, isoproterenol, verapamil, dexamethasone and mepacrine are not mediated by interference with membrane phosphoinositide breakdown.

Animals↗
PubMed2004

Solution structure and backbone dynamics of the pleckstrin homology domain of the human protein kinase B (PKB/Akt). Interaction with inositol phosphates.

The programmed cell death occurs as part of normal mammalian development. The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of extracellular stimuli. Recently, the ability of trophic factors to promote survival have been attributed, at least in part, to the phosphatidylinositide 3'-OH kinase (PI3K)/Protein Kinase B (PKB, also named Akt) cascade. Several targets of the PI3K/PKB signaling pathway have been identified that may underlie the ability of this regulatory cascade to promote cell survival. PKB possesses a N-terminal Pleckstrin Homology (PH) domain that binds specifically and with high affinity to PtIns(3,4,5)P(3) and PtIns(3,4)P(2), the PI3K second messengers. PKB is then recruited to the plasma membrane by virtue of its interaction with 3'-OH phosphatidylinositides and activated. Recent evidence indicates that PKB is active in various types of human cancer; constitutive PKB signaling activation is believed to promote proliferation and increased cell survival, thereby contributing to cancer progression. Thus, it has been shown that induction of PKB activity is augmented by the TCL1/MTCP1 oncoproteins through a physical association requiring the PKB PH domain. Here we present the three-dimensional solution structure of the PH domain of the human protein PKB (isoform beta). PKBbeta-PH is an electrostatically polarized molecule that adopts the same fold and topology as other PH-domains, consisting of a beta-sandwich of seven strands capped on one top by an alpha-helix. The opposite face presents three variable loops that appear poorly defined in the NMR structure. Measurements of (15)N spin relaxation times and heteronuclear (15)N[(1)H]NOEs showed that this poor definition is due to intrinsic flexibility, involving complex motions on different time scales. Chemical shift mapping studies correctly defined the binding site of Ins(1,3,4,5)P(4) (the head group of PtIns(3,4,5)P(3)), as was previously proposed from a crystallographic study. More interestingly, these studies allowed us to define a putative alternative low-affinity binding site for Ins(1,4,5)P(3). The binding of this sugar to PKBbeta-PH might also involve non-specific association that could explain the stabilization of the protein in solution in the presence of Ins(1,4,5)P(3).

Apoptosis↗
PubMed1970

Metabolism of Inositol Phosphates: I. Phytase Synthesis during Germination in Cotyledons of Mung Beans, Phaseolus aureus.

The degradation of phytin in germinating mung bean seeds has been found to be associated with the increased activity of phytase in the cotyledon. In the differentiated embryo the increase of this activity is very low all throughout the growth periods studied. Phytase appears in the cotyledon during germination. No activity has been detected in the cotyledons of unsoaked seeds. Cycloheximide (10(-6) M) inhibits the appearance of phytase by 61% during 24 and 48 hours after the start of germination. This phytase increase is dependent on the synthesis of new RNA in the cotyledon. Synthesis of DNA is not detected in the cotyledon during germination.

Journal Article↗
PubMed1998

Inhibition of carbachol-induced inositol phosphate accumulation in the embryonic retina promoted by kainate and veratridine.

In the present study, we report that low concentrations of the glutamate ionotropic agonist kainate decreased the turnover of [3H]-phosphoinositides ([3H]-InsPs) induced by muscarinic receptors in the chick embryonic retina. When 100 microM carbachol was used, the estimated IC50 value for kainate was 0.2 microM and the maximal inhibition of approximately 50% was obtained with 1 microM or higher concentrations of the glutamatergic agonist. Our data also show that veratridine, a neurotoxin that increases the permeability of voltage-sensitive sodium channels, had no effect on [3H]-InsPs levels of the embryonic retina. However, 50 microM veratridine, but not 50 mM KCl, inhibited approximately 65% of the retinal response to carbachol. While carbachol increased [3H]-InsPs levels from 241.2 +/- 38.0 to 2044.5 +/- 299.9 cpm/mg protein, retinal response decreased to 861.6 +/- 113.9 cpm/mg protein when tissues were incubated with carbachol plus veratridine. These results suggest that the accumulation of phosphoinositides induced by activation of muscarinic receptors can be inhibited by the influx of Na+ ions triggered by activation of kainate receptors or opening of voltage-sensitive sodium channels in the chick embryonic retina.

Animals↗