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PubMed1987

Formation of inositol 1,3,4,6-tetrakisphosphate during angiotensin II action in bovine adrenal glomerulosa cells.

Angiotensin II stimulates the formation of several inositol polyphosphates in cultured bovine adrenal glomerulosa cells prelabelled with [3H] inositol. Analysis by high performance anion exchange chromatography of the inositol-phosphate compounds revealed the existence of two additional inositol tetrakisphosphate (InsP4) isomers in proximity to Ins-1,3,4,5-P4, the known phosphorylation product of Ins-1,4,5-trisphosphate and precursor of Ins-1,3,4-trisphosphate. Both of these new compounds showed a slow increase after stimulation with angiotensin II. The structure of one of these new InsP4 isomers, which is a phosphorylation product of Ins-1,3,4-P3, was deduced by its resistance to periodate oxidation to be Ins-1,3,4,6-P4. The existence of multiple cycles of phosphorylation-dephosphorylation reactions for the processing of Ins-1,4,5-P4 may represent a new aspect of the inositol-lipid related signalling mechanism in agonist-activated target cells.

Adrenal Glands↗
PubMed1987

Bradykinin-stimulated changes in inositol phosphate mass in renal papillary collecting tubule cells.

The effect of bradykinin on changes in the chemical levels of myo-inositol polyphosphates in renal papillary collecting tubules was investigated. Myo-inositol phosphate mass was determined by means of an enzymatic, fluorometric assay. Bradykinin induced increases in myo-inositol mono-, bis-, and trisphosphate which were both time and concentration dependent. Furthermore, the magnitude of the chemical levels of myo-inositol monophosphate formed were unlikely to be accounted for solely by the formation and degradation of myo-inositol trisphosphate. These observations are consistent with the concomitant hydrolysis of phosphatidylinositol and phosphatidylinositol bisphosphate. This study also confirms, in freshly isolated renal tubules, observations regarding bradykinin-induced phosphatidylinositol bisphosphate hydrolysis made previously in radiolabeled cultures.

Animals↗
PubMed1989

Inhibition by nicardipine of endothelin-mediated inositol phosphate formation and Ca2+ mobilization in smooth muscle cell.

We have investigated the effects of endothelin on phosphoinositide metabolism and Ca2+ mobilization in cultured A10 cells. Endothelin stimulated a significant increase in inositol phosphate formation in a time- and dose-dependent manner. IP3 was significantly elevated by 30 sec and reached a 2.0-fold above control at 1 min. The EC50 for endothelin was 0.5 nM. The initiation of inositol phosphate formation was independent of extracellular Ca2+, and the Ca2+ ionophore, A23187, did not stimulate IP3 formation. However, the sustained elevation of inositol phosphates was partially inhibited by incubating cells in buffer lacking Ca2+ or in buffer containing nicardipine. Endothelin mobilized both intracellular and extracellular Ca2+ reaching a peak intracellular concentration of 350 +/- 11 nM by 1 min when cells were bathed with Ca2+-complete buffer. Intracellular Ca2+ remained 2-fold above baseline for at least 15 min. In contrast, when cells were exposed to endothelin in Ca2+-free buffer, the peak value of [Ca2+]i was 195 +/- 20 nM and returned to baseline by 2 min. Nicardipine completely blocked the influx of extracellular Ca2+ but did not interfere with the mobilization of intracellular stores. We conclude that endothelin produces a rapid and sustained elevation in inositol phosphate formation. The rapid production of IP3 is consistent with the time course for mobilization of intracellular Ca2+. Elevated cytosolic Ca2+ levels are maintained by the influx of extracellular Ca2+ through a nicardipine-sensitive Ca2+ channel and are involved in the sustained formation of inositol phosphates. These data provide an explanation for the sustained, nicardipine-inhibitable contraction of coronary artery strips induced by endothelin.

Animals↗
PubMed1990

Effect of angiotensin II and III on inositol polyphosphate production in differentiated NG108-15 hybrid cells.

Neuroblastoma x glioma hybrid cells (NG108-15), differentiated by treatment with 1.5% dimethyl sulfoxide (DMSO) and 0.5% fetal bovine serum, were used to measure the effect of angiotensin II and III (ANG II and ANG III) on the generation of inositol polyphosphates. ANG II increased the synthesis of inositol monophosphates (IP1), inositol diphosphates (IP2), and inositol trisphosphates (IP3) with maximal responses observed at 300, 120, and 30 sec, respectively. The percent increases above basal values at the maximal responses were 140% +/- 9% (IP1), 142% +/- 4% (IP2), and 132% +/- 4% (IP3). This effect was not attenuated by pretreatment of the cells with pertussis toxin. Furthermore, both ANG II and ANG III increased the production of inositol polyphosphates in a dose-dependent manner with ED50 values of 145 nM and 11 nM, respectively. We conclude that differentiated NG108-15 cells express an ANG III selective receptor that mediates phosphatidylinositol breakdown through a pertussis toxin insensitive G-protein.

Angiotensin II↗
PubMed1991

Glucocorticoids inhibit formation of inositol phosphates in macrophages.

Glucocorticoids inhibited the zymosan-induced formation of inositol phosphates in macrophages. No inhibition was observed with progesterone. Inhibitors of protein (cycloheximide) and RNA (actinomycin D) synthesis exhibited similar inhibitory effects. The activity of phospholipase C in subcellular fractions was not altered by hormone treatment of the cells. However, the incorporation of inositol into membrane lipids was reduced by dexamethasone. These data indicate that glucocorticoids are able to inhibit the formation of inositol phosphates; the effect of the hormone is rather due to an inhibition of the incorporation of inositol in membrane lipids than to an inhibition of phospholipase C. The anti-inflammatory action of glucocorticoids may, therefore, also be attributed to their effect on the polyphosphoinositide cycle and inositol phosphate-mediated processes.

Animals↗
PubMed1990

Differential effects of elevated calcium ion concentrations on inositol phospholipid responses in mouse and rat cerebral cortical slices.

Inositol phospholipid turnover in cerebral cortical slices from mouse and rat was assessed using a [3H]inositol pre-labelling technique followed by anion exchange chromatography to isolate [3H]inositol phosphates ([3H]InsP chi). In both mouse and rat cerebral cortical slices, elevating the CaCl2 concentration of the Krebs medium from 1.3 to 4 mM did not significantly enhance the accumulation of [3H]InsP chi in the absence of any stimulus, or in the presence of glutamate (3 mM), depolarizing concentrations of KCl (25 mM), 5-hydroxytryptamine (0.3 mM), the calcium ionophore A23187 (33 microM) or carbachol (1 mM). However, the accumulations of [3H]InsP chi induced by histamine (1 mM) or noradrenaline (0.1 mM) were significantly increased by between 95 and 178% in cerebral cortical slices from both species by the elevation of extracellular calcium. Analysis of the individual inositol phosphates revealed that elevated ambient calcium enhanced the histamine-generated accumulations of [3H]InsP2, [3H]InsP3 and [3H]InsP4 by up to two-fold, while only the [3H]InsP3 response to carbachol was significantly increased. Under the same conditions, histamine, but not carbachol, selectively increased the accumulation of [3H]PtdInsP2 by up to 50%. The [3H]InsP chi responses to histamine and noradrenaline in combination with the calcium ionophore A23187 were greater-than-additive, inferring an enhancement of the receptor response by raised intracellular calcium. However, the combination of A23187 with glutamate or KCl resulted in significantly less-than-additive [3H]InsP chi responses. The [3H]InsP chi response to carbachol or 5-hydroxytryptamine was not significantly altered in the presence of A23187. Taken together, these results indicate heterogeneity between the mechanisms of inositol phospholipid turnover induced by these various stimuli in mammalian cerebral cortical slices.

Animals↗
PubMed1986

Noradrenaline-stimulated inositol phospholipid breakdown in rat dorsal lateral geniculate nucleus neurones.

Noradrenaline-stimulated inositol phospholipid breakdown in matched vibratome sections through the rat dorsal lateral geniculate nucleus (dLGN). The response was measured as a large accumulation of [3H]inositol labelled inositol monophosphate and was mediated via activation of alpha 1-adrenergic receptors. Accumulation of [3H]inositol phosphates was reduced in kainic acid-lesioned animals, indicating that this response occurred within dLGN neurones and not afferent terminals. The results implicate inositol phospholipid breakdown as part of the mechanism of noradrenergic neurotransmission within the dLGN.

Animals↗
PubMed1990

Myo-inositol transport into endothelial cells derived from nervous system microvessels.

Myo-inositol, the precursor in the biosynthesis of inositol phospholipids and inositol phosphates, is found in many tissues at concentrations well above its concentration in the plasma, but the highest concentrations are in the central nervous system and the neuroretina. We describe an active, sodium gradient-dependent transport of myo-inositol into cultured endothelial cells derived from bovine retinal microvessels. Transport is inhibited by cytochalasin B, and phloridzin greater than phloretin. Mannitol, sorbitol, and fructose do not inhibit uptake, but D-galactose. inhibits uptake greater than L-glucose greater than D-glucose. The apparent Km of this transport system is 311 +/- 47 (S.D.) microM and the apparent Vmax is 40.8 +/- 2.8 (S.D.) pmol.mg protein-1.min-1. This transport system may be a key in the maintenance of this tissue concentrations as it could concentrate myo-inositol from the plasma into the extracellular spaces of the eye and central nervous system.

Animals↗
PubMed1985

Activation of alpha 1-adrenoceptors increases [3H]inositol metabolism in rat vas deferens and caudal artery.

Rings of rat vas deferens and caudal artery were incubated with [3H]inositol in Krebs-Ringer bicarbonate buffer containing 10 mM lithium chloride, and the production of water-soluble [3H]inositol phosphates was monitored. Norepinephrine increased [3H]inositol phosphate accumulation 7-fold in rings from vas deferens and 3-fold in rings from caudal artery. Epinephrine, phenylephrine and methoxamine were as effective as norepinephrine, suggesting that these drugs are full agonists in causing this response. Prazosin, phentolamine and yohimbine completely blocked the stimulation by norepinephrine in both tissues with potencies typical of blockade of alpha 1-adrenoceptors. Despite a substantial receptor reserve for alpha 1-adrenoceptor mediated contractile responses, clonidine, p-amino-clonidine, phenylpropanolamine and ephedrine can only cause a partial contractile response in rat vas deferens. However, all of these partial agonists were either as effective or more effective in increasing [3H]inositol phosphate accumulation in rat vas deferens as they were in activating a contractile response. These data suggest that alpha 1-adrenoceptors increase phosphatidylinositol turnover in rat vas deferens and caudal artery, and that there may be a receptor reserve for alpha 1-adrenoceptor mediated increases in [3H]inositol phosphate accumulation in these smooth muscles.

Adrenergic alpha-Agonists↗
PubMed1987

Does the inositol tris/tetrakisphosphate pathway exist in rat heart?

Appearance of two isomers of inositol trisphosphate (InsP3) was observed when [3H]inositol prelabelled rat heart ventricles were stimulated for 10 and 30 s with noradrenaline. In contrast, inositol tetrakisphosphate (InsP4) could not be detected. However the existence of the inositol tris/tetrakisphosphate pathway was demonstrated by studying [3H]inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) metabolism in a soluble fraction of rat heart. There, [3H]Ins-1,4,5-P3 was phosphorylated to form [3H]Ins-1,3,4,5-P4. Raising [Ca2+] from 1 nM to 1 microM increased InsP3 kinase activity by 2-fold (EC50 for Ca2+ approx. 56 nM). This effect appeared to be due to an increase of the apparent Vmax of the enzyme while the apparent Km was unchanged.

1-Phosphatidylinositol 4-Kinase↗
PubMed1989

Signal transduction in EJ-H-ras-transformed cells: de novo synthesis of diacylglycerol and subversion of agonist-stimulated inositol lipid metabolism.

We examined the level of 1,2-diacylglycerol and inositol phosphates in normal and EJ-H-ras-transformed BALB/3T3 fibroblasts by prelabelling the cells with [3H]glycerol, [3H]inositol, [14C]glucose, [14C]arachidonic acid, and [14C]palmitic acid. Steady-state level of inositol phosphates, however, was the same in control and transformed cells. Diacyglycerol labelling by [14C]arachidonic acid was the same in control and transformed cells. Insulin dramatically increased diacylglycerol labeling by [14C]glucose in normal cells, whereas it did not affect ras-transformed fibroblasts. Neurotransmitter-induced inositol lipid turnover was greatly enhanced in ras-transformed cells; conversely, platelet-derived growth factor and thrombin-stimulated normal cells to a greater extent than transformed fibroblasts. Taken together these results suggest that ras transformation may induce multifarious effects on signal transduction: it may cause de novo synthesis of diacylglycerol and subversion of neurotransmitter and growth factor receptor coupling to inositol lipid metabolism.

Animals↗
PubMed1991

Inositol phosphate formation in uterine tissue from two species of reptiles is stimulated by arginine vasotocin and influenced by stage of reproduction.

Phosphoinositide hydrolysis, resulting in inositol trisphosphate (IP3) and diacylglycerol (DG) formation, has been implicated in oxytocin-stimulated pulsatile secretion of prostaglandin F2 alpha (PGF2 alpha) from uterine endometrium of sheep and other mammals. In reptiles, arginine vasotocin (AVT) stimulates uterine secretion of PGF2 alpha. These studies investigated the ability of AVT to stimulate incorporation of [3H]inositol into inositol mono-, bis-, and trisphosphates in two reptilian species. In Experiment 1, AVT stimulated (P less than 0.01) IP formation in uterine from late-gravid (150 to 291%) and postpartum (104 to 363%) Yarrow's spiny lizards (Sceloporus jarrovi). Inositol phosphate formation, in response to AVT, was greater (P less than 0.01 for IP3 and P less than 0.05 for total IP) for gravid (stage 40 embryos) and postpartum (1-2 days) lizards near the time of parturition than for lizards at other stages (stage 38-39 embryos or 7 days postpartum). Inositol phosphate formation was greater (P less than 0.05) in uterine tissue from gravid than from postpartum lizards. In Experiment 2, basal IP formation and the response to AVT were the greatest (P less than 0.01) in endometrium from late-gravid American alligators (Alligator mississippiensis). AVT stimulated (P less than 0.02) IP synthesis in uterine endometrium from vitellogenic (136 to 394%), early-gravid (7 to 270%), late-gravid (315 to 1002%), postpartum (86 to 313%), and nonreproductive (292 to 322%) alligators. Results indicate that (1) AVT stimulates IP formation in the uterus of reptiles; (2) uterine IP formation increases in late-gravid reptiles; and (3) increased responsiveness to AVT may occur at parturition or oviposition.

Animals↗
PubMed1990

Insulin stimulates inositol incorporation in hippocampus of lean but not obese Zucker rats.

We have previously reported that intraventricular insulin is ineffective in decreasing the body weight of obese (fa/fa) Zucker rats. In the present study, we report that insulin at concentrations of 1 and 5 nM significantly stimulates incorporation of 3H-myoinositol into inositol phosphates (29 +/- 5% and 20 +/- 6% stimulation over control levels) and membrane inositol lipids (29 +/- 4% and 20 +/- 6% stimulation over control levels) within hippocampal slices from lean (Fa/Fa) Zucker rats (n = 3 preparations). Smaller but significant stimulations were observed in the Fa/fa Zucker rat (n = 5) hippocampus [10 +/- 3 and 13 +/- 4% stimulation over control levels (inositol phosphates) and 10 +/- 4 and 14 +/- 3% stimulation over control levels (inositol lipids) with 1 and 5 nM insulin]. Insulin had no effect on 3H-inositol incorporation into hippocampal slices from obese (fa/fa) Zucker rats (n = 5). No difference in insulin binding to hippocampal membranes was observed among the three genotypes. These findings confirm the behavioral observation of insulin insensitivity within the fa/fa Zucker CNS and suggest that this insensitivity may be gene-dose-related.

Animals↗
PubMed1994

Myo-inositol trisphosphate-mediated calcium release from internal stores of Entamoeba histolytica.

Calcium mobilisation from internal stores of the parasitic protozoan Entamoeba histolytica was studied by fluorescence measurements of the calcium indicator quin 2 and 45Ca2+ incorporation studies in saponin-permeabilised amoebae. Prior energy-dependent calcium sequestration was found to be necessary for subsequent release of calcium by inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). Both Ins(1,4,5)P3 and inositol 2,4,5-trisphosphate (Ins(2,4,5)P3) could release calcium equally well from permeabilised E. histolytica with similar EC50 (concentration which produced half maximal release) values for calcium release. Ins(1,4,5)P3-mediated calcium release occurred from a vesicular store, was sensitive to prior treatment by heparin and was attenuated by prior addition of a lower concentration of Ins(1,4,5)P3. cAMP failed to influence inositol trisphosphate induced calcium release, indicating the absence of control mechanisms through cAMP-dependent phosphorylation. GTP neither induced calcium release nor could potentiate inositol trisphosphate mediated calcium mobilisation. A saturating concentration of Ins(1,4,5)P3 could release 50% of radiolabelled calcium sequestered by energy-dependent mechanisms in E. histolytica. The energy-dependent calcium sequestration was inhibited by vanadate and the calcium antagonist Diltiazem but not by dicyclohexylcarbodiimide (DCCD), suggesting the involvement of an endoplasmic reticulum-like structure in calcium storage. Binding studies showed specific association of [3H]Ins(1,4,5)P3 to crude membrane fractions of E. histolytica, which was significantly inhibited by heparin in a dose-dependent manner. IC50 (concentration which produced half-maximal inhibition) values for displacement of radiolabelled Ins(1,4,5)P3 binding by unlabelled Ins(1,4,5)P3 and Ins(2,4,5)P3 were estimated to be 0.99 microM for both isomers. Our results suggested that Ins(1,4,5)P3-mediated calcium release from internal stores of E. histolytica most probably occurred in an inositol trisphosphate receptor-dependent manner.

Animals↗
PubMed1988

Age-related impairment in rat parotid cell alpha 1-adrenergic action at the level of inositol trisphosphate responsiveness.

Alpha 1-Adrenergic-stimulated calcium efflux from rat parotid cell aggregates declines approx. 40% between 3 and 24 months of age, with the bulk of the reduction occurring between 12 and 24 months. Intracellular free calcium levels following alpha 1-adrenoceptor stimulation are also reduced about 40% between 3 and 24 months. No significant age differences in stimulation of inositol mono-, bis- or trisphosphate production are observed. However, the ability of inositol trisphosphate to directly stimulate calcium efflux is reduced by about 50% with increasing age. Concentrations of this inositol phosphate required for maximal calcium release do not change between 3 and 24 months. Differences in response are not due to a reduction in uptake of inositol trisphosphate into older cells, but suggest an age-related defect in the ability of inositol trisphosphate to liberate calcium from intracellular stores. Such dysfunction may be at least partially responsible for impaired alpha 1-adrenergic responsiveness during aging.

Age Factors↗
PubMed1981

Inhibition by Ca2+ of the incorporation of myo-inositol into phosphatidylinositol.

The incorporation of myo-[2-3H]inositol into phosphatidylinositol of the aorta and the vas deferens was measured and the effects of Ca2+ and other divalent cations were determined. When incubated in normal Krebs-Ringer buffer, only negligible radioactivity was incorporated into aorta slices. Mn2+ increased the incorporation greatly. The enhanced incorporation was attributable to an increase in CDP-diglyceride:inositol transferase activity, rather than the myo-inositol exchange reaction. Transferase activity was increased 20-fold by 1 mM Mn2+, in the presence of 20 mM Mg2+. The Mn2+-stimulated activity was strongly inhibited by Ca2+. In the absence of Mn2+, but presence of 20 mM Mg2+, transferase activity was inhibited 80% by 0.01 mM Ca2+. Removal of endogenous Ca2+ from the tissue by ionophore A23187 and EGTA increased the incorporation of myo-[2-3H]inositol into phosphatidylinositol. These findings indicate that Ca2+ inhibited the synthesis of phosphatidylinositol. The proposed action of cholinergic and alpha-adrenergic agonists in enhancing the degradation and turnover of phosphatidyl-inositol and in provoking the influx of Ca2+ should be unfavorable to the recovery of cellular phosphatidylinositol content.

Animals↗
PubMed1992

Postischemic binding of [3H]phorbol 12,13-dibutyrate and [3H]inositol 1,4,5-trisphosphate in the gerbil brain: an autoradiographic study.

Postischemic alteration of second messenger systems was investigated in the Mongolian gerbil, utilizing [3H]phorbol 12,13-dibutyrate and [3H]inositol 1,4,5-trisphosphate receptor autoradiography. Transient ischemia was induced for 10 min, and animals were allowed to survive for various recirculation periods of up to one month. [3H]Phorbol 12,13-dibutyrate binding in selectively vulnerable areas showed no significant change 1-24 h after ischemia except for a transient decline in a few regions. Thereafter, the binding in most of the selectively vulnerable areas showed significant alteration 48 h or seven days after ischemia. Interestingly, dentate molecular layer which was resistant to ischemia showed a significant elevation in the number of [3H]phorbol 12,13-dibutyrate binding sites. One month after ischemia, [3H]phorbol 12,13-dibutyrate binding showed significant reduction only in the striatum and the hippocampal CA1 sector where severe neuronal damage was seen morphologically. A significant elevation in the number of [3H]phorbol 12,13-dibutyrate binding sites was still seen in the dentate molecular layer one month after ischemia. In contrast, [3H]inositol 1,4,5-trisphosphate binding showed significant reduction in the selectively vulnerable regions 1-24 h after ischemia. Thereafter, [3H]inositol 1,4,5-trisphosphate binding in most of the selectively vulnerable areas markedly decreased up to one month after ischemia. In the dentate molecular layer, [3H]inositol 1,4,5-trisphosphate binding also showed significant reduction during recirculation except for a slight recovery 48 h and seven days after ischemia. One month after ischemia, the binding in all regions showed significant reduction. These results suggest that postischemic alteration of two second messenger (protein kinase C and inositol 1,4,5-trisphosphate) binding sites was produced with different processes in selectively vulnerable areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Neuronal inositol 1,4,5-trisphosphate receptor localized to the plasma membrane of olfactory cilia.

Both the cyclic adenosine 3',5'-monophosphate and the phosphoinositide second messenger systems are involved in olfactory signal transduction. The inositol 1,4,5-trisphosphate receptor is one of the principal intracellular calcium channels responsible for mobilizing stored calcium. The precise location of the 1,4,5-trisphosphate receptor (endoplasmic reticulum vs surface) and its role in the events of olfactory signal transduction need to be defined. By light microscopic and confocal immunohistochemistry we show expression of the olfactory-enriched G-protein, G(olf), associated with cyclic AMP responses, and of the inositol 1,4,5-trisphosphate receptor in the dendritic projections and cilia of essentially all olfactory receptor neurons, indicating that individual neurons express components of both second messenger systems. By immunoelectron microscopy, we demonstrate that the inositol 1,4,5-trisphosphate receptor is localized to the surface membrane of rat olfactory cilia. This is the first morphological demonstration of the surface membrane localization of inositol 1,4,5-trisphosphate receptor in olfactory cilia. Our findings, taken in conjunction with electrophysiological data from other workers, are supportive of the inositol 1,4,5-trisphosphate receptor playing a novel role in regulating calcium flux at the ciliary surface membrane.

Animals↗