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PubMed1990

Effects of insulin on inositol phosphate production in cultured rat hepatocytes.

Addition of vasopressin (100 nM) to rat hepatocytes prelabelled with [3H]inositol stimulated the production of inositol phosphates in the presence of 20 mM Li+. Preincubation of hepatocytes with insulin (50 nM) or glucagon (10 nM) had no significant effect alone but enhanced the effects of vasopressin after a lag period of at least 1 min. The effects of insulin and glucagon appeared additive in this respect. Insulin also enhanced the norepinephrine-mediated stimulation of inositol phosphate accumulation. The enhancement by insulin of the effects of vasopressin required at least 0.5-5 nM insulin and did not involve changes in [3H]inositol lipid labelling or IP3 phosphatase activity. The effect of insulin appeared insensitive to prior treatment of hepatocytes with pertussis toxin (200 ng/ml for 18-24 h) or cholera toxin (100 ng/ml for 3-4 h). The glucagon enhancement of the effects of vasopressin was not affected by pertussis toxin but was mimicked by cholera toxin. The response of hepatocytes to vasopressin in the absence of Li+ was smaller and more transient. Under these conditions a 5 min prior incubation with insulin inhibited the stimulation by vasopressin of inositol phosphate accumulation. A similar inhibitory effect of prior insulin exposure on the transient activation by vasopressin of exogenous phosphatidylinositol 4,5-bisphosphate breakdown by hepatocyte homogenates was also seen. These data indicate that insulin, although having no effect on basal inositol phosphate accumulation, can either enhance or antagonise the effects of vasopressin in primary rat liver hepatocyte cultures depending on the experimental conditions.

Animals↗
PubMed1987

Evidence for a lack of inositol--(1,4,5)trisphosphate kinase activity in norepinephrine-perfused rat hearts.

The products of the phosphatidylinositol turnover pathway in norepinephrine-perfused hearts have been examined using high performance liquid chromatography. Inositol-1 phosphate, inositol-(1,4)bisphosphate and inositol-(1,4,5)-trisphosphate were all increased in response to norepinephrine stimulation. However, at perfusion times from 5 sec to 20 min there was no appearance of inositol-(1,3,4,5)tetrakisphosphate or inositol-(1,3,4)trisphosphate. This suggests the absence of the inositol-(1,4,5)trisphosphate phosphorylation/dephosphorylation pathway in heart and demonstrates that this secondary pathway is not essential to the functioning of the phosphatidylinositol turnover cycle.

Adrenal Glands↗
PubMed1988

Bombesin stimulates inositol polyphosphate production in GH4C1 pituitary tumor cells: comparison with TRH.

The hormones bombesin and thyrotropin-releasing hormone (TRH) stimulated formation of inositol- monophosphate, bisphosphate, trisphosphate and tetrakisphosphate with parallel time courses in GH4C1 cells, while a more polar inositol polyphosphate peak, consisting of inositol-pentakisphosphate and perhaps also inositol-hexakisphosphate, was unaffected by either hormone. Although bombesin and TRH had similar potencies in stimulating inositol trisphosphate production (Km = 30 nM and 40 nM, respectively), TRH was significantly more efficacious than bombesin. Maximal stimulation of inositol-1,4,5-trisphosphate formation by TRH was not further increased by addition of a maximally effective dose of bombesin, suggesting that the two hormones act through stimulation of a common pool of phospholipase C, and this enzyme pool can be fully stimulated by TRH, alone.

Animals↗
PubMed1989

Inositol trisphosphate independent increase of intracellular free calcium and amylase secretion in pancreatic acini.

It is generally believed that the activation of various cell surface receptors results in the phospholipase C-catalyzed production of inositol trisphosphate which, in turn, increases the intracellular concentration of free Ca2+ by stimulating its release from nonmitochondrial sources. We have investigated both the production of inositol trisphosphate and changes in intracellular Ca2+ concentration in rat pancreatic acini in response to caerulein and CCK-JMV-180, two analogs of cholecystokinin. Both of these analogs cause comparable increases in the rate of amylase secretion and in intracellular Ca2+ concentration but their effects on inositol phosphate generation are dramatically different; caerulein stimulates significant production of inositol phosphates within 1 min of its addition, whereas no detectable levels of inositol phosphates were generated within the same time after addition of CCK-JMV-180. These results suggest that the CCK-JMV-180 stimulated release of intracellular Ca2+ is not mediated by inositol trisphosphate but some other as yet unidentified messenger.

Amylases↗
PubMed1992

Growth factors promote inositol uptake in BC3H1 cells.

BC3H1 cells induced to differentiate by serum withdrawal were found to incorporate substantially less [3H]inositol into their phosphoinositides than cells induced to differentiate by growth in the presence of high serum. This decrease was found to be due to a decline in the rate of [3H]inositol uptake by the serum-starved cells. Addition of purified growth factors such as TGF-beta, EGF and FGF to these cells promoted inositol uptake and lead to an increase in the incorporation of [3H]inositol into phosphoinositides. Stimulation of inositol uptake by TGF-beta required at least a 24 hr exposure to the growth factor. These data indicate that growth factors regulate phosphoinositide metabolism at many different levels including at the level of inositol uptake.

Animals↗
PubMed1987

Effects of calcium depletion on norepinephrine- and A23187-induced stimulation of inositol phosphate formation.

The role of calcium in the stimulation of phosphoinositide (PIn) hydrolysis by norepinephrine and the calcium ionophore A23187 was investigated in chopped cerebral cortex in which the PIns had been labeled previously with ([3H]myo-inositol. The accumulation of the newly formed [3H]inositol phosphate ([3H]IPs) was used as an index of PIn hydrolysis. Norepinephrine produced a concentration-related increase in the accumulation of [3H]inositol-phosphates ([3H]IP), and this effect was only partially antagonized by omission of calcium from the incubation medium. Norepinephrine had relatively little effect on the accumulation of [3H]inositol 1,4-bisphosphate [3H]IP2 and inositol 1,4,5-triphosphate and/or inositol 1,3,4-trisphosphate ([3H]IP3). A23187 also increased the accumulation of [3H]IP but this effect was not antagonized by omission of calcium from the incubation medium. When the tissue had been washed extensively with EGTA, the basal levels of [3H]IP, [3H]IP2 and [3H]IP3 were decreased markedly, and the effects of both norepinephrine and A23187 were antagonized. Addition of calcium back to the depleted tissue led to an increase in the basal level of [3H]IPs as well as restoration of the stimulation produced by norepinephrine and A23187. The calcium threshold for the PIn effect was 0.1 microM. Additional calcium did not affect markedly the stimulation of accumulation of [3H]IP produced by norepinephrine and A23187. The results suggest that there is an absolute calcium requirement for PIn phosphodiesterase which is attained at 0.1 microM Ca2+. A23187 can stimulate the accumulation of [3H]IP perhaps by providing access of another form of the enzyme to artificially high concentrations (millimolar range) of calcium.

Animals↗
PubMed1990

Modulation of carbachol-induced inositol phosphate formation in bovine tracheal smooth muscle by cyclic AMP phosphodiesterase inhibitors.

An investigation was made of a range of agents capable of elevating tissue cyclic AMP levels, or acting as a stable analogue of cyclic AMP, upon carbachol induced inositol phosphate responses in bovine tracheal smooth muscle slices. Whereas the beta 2 adrenoceptor agonist salbutamol (1 microM) and the membrane permeable analogue of cyclic AMP, 8-bromo-cyclic AMP (1 mM) were without effect upon total [3H]inositol phosphate formation induced by carbachol, 3-iso-butyl-1-methylaxanthine (IBMX) (EC50 140 microM), the high Km, cyclic AMP selective phosphodiesterase inhibitor rolipram (EC50 41 microM) and theophylline (EC50 76 microM) all inhibited the inositol phosphate response to low (1 microM) concentrations of carbachol. IBMX (IC50 13 microM), rolipram (IC50 4.6 microM) and theophylline (IC50 180 microM) all relaxed bovine tracheal muscle strips precontracted with methacholine (1 microM). The adenylate cyclase activator forskolin (1 microM), produced a much smaller (10% inhibition) effect upon inositol phosphate formation induced by carbachol. Carbachol (1 microM-1 mM) did not inhibit forskolin induced [3H]cyclic AMP formation. An inhibitor of the cyclic GMP preferring phosphodiesterase isozyme, M&B 22948 (1-100 microM), was without effect upon either carbachol induced inositol phosphate formation or trachealis tone. It is concluded that IBMX, rolipram and theophylline inhibit carbachol stimulated inositol phosphate formation, possibly through a cyclic AMP independent mechanism.

1-Methyl-3-isobutylxanthine↗
PubMed1991

The agonist-stimulated accumulation of inositol phosphates is attenuated in neutrophils from male patients under chronic lithium therapy.

Neutrophils from 22 patients (11 men, 11 women) under chronic lithium therapy and from 22 age- and sex-matched healthy controls were assessed for the activity of the agonist-stimulated inositol-phospholipid second messenger-producing system. [3H]inositol-labeled cells were stimulated with the chemotactic peptide formylmethionylleucylphenyl-alanin (fMLP). The fMLP-evoked increase in the accumulation of [3H]inositol phosphates was significantly attenuated in neutrophils from chronically lithium-treated male but not female patients. Furthermore, the fMLP-stimulated accumulation of inositol phosphates was attenuated in neutrophils from male volunteers, when the labeling of the cells with [3H]inositol was performed in the presence of 1mM Li (4 hr, 37 degrees C). However, the presence of lithium ions during the labeling did not further reduce the already diminished response of neutrophils from patients under lithium therapy. These results suggest that lithium treatment induces an inhibition of the agonist-evoked breakdown of inositol phospholipids in human cells, as already shown for rat brain slices.

Adult↗
PubMed1987

Serotonergic and cholinergic stimulation of inositol phosphate formation in the rabbit retina. Evidence for the presence of serotonin and muscarinic receptors.

A direct assay which involves prelabelling with [3H]inositol has been performed to characterize receptor-mediated breakdown of inositol phospholipids in the rabbit retina. In the presence of 10 mM lithium, the receptor agonists, carbachol and serotonin (5-HT), evoked an increase in the accumulation of tritiated inositol phosphates in a dose-dependent manner. A variety of 5-HT and other antagonists were used to show that at least part of the 5-HT-induced response is mediated by 5-HT2 receptor sites, adding weight to the theory that 5-HT plays a neurotransmitter role in the mammalian retina. The very high rate of carbachol-stimulated inositol phosphate accumulation observed in retinas from young animals (10 days) decreases significantly during development of the rabbit to the adult stage. In contrast 5-HT only induces significant stimulation of inositol phosphate accumulation in retinas of animals matured to at least 17 days. Separation of total accumulated inositol phosphates (after stimulation with both carbachol and 5-HT) showed that the vast majority of tritium label was associated with the monophosphate fraction.

Age Factors↗
PubMed1985

Dihydropyridine calcium channel activators and antagonists influence depolarization-evoked inositol phospholipid hydrolysis in brain.

Increased inositol phospholipid hydrolysis induced by elevated extracellular K+ was directly monitored by assaying [3H]inositol phosphate accumulation following prelabelling of cerebral cortical slices with [3H]inositol. Depolarization evoked by K+ increased [3H]inositol phosphate accumulation with a 2-3-fold stimulation observed at 18 mM K+. Higher concentrations of K+ failed to further increase accumulation though a suppression of the incorporation of [3H]inositol into phospholipid at higher K+ could complicate these results. Slices incubated with the dihydropyridine calcium channel activator BAY-K-8644 resulted in a much increased response to 12 mM and 18 mM K+ with substantially smaller enhancement of basal (6 mM) or much higher (30 and 55 mM) K+. The [3H]inositol phosphate response induced by 18 mM K+ + 1 microM BAY-K-8644 was markedly reduced when incubations were performed in the presence of reduced Ca2+. Similarly, preincubation of slices with the dihydropyridine antagonist PN-200-110 suppressed the response to K+ and to K+ + BAY-K-8644. This effect was stereospecific with the (+)-enantiomer being at least 100-fold more potent than the (-)-enantiomer. These data provide primary evidence for functional dihydropyridine-sensitive calcium channels in brain.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Thrombin stimulates inositol phosphate formation, intracellular calcium fluxes and DNA synthesis in cultured fetal human non-pigmented ciliary epithelial cells.

Thrombin at concentrations as low as 20 pM (0.002 U ml-1) was found to stimulate inositol phosphate levels in cultured human non-pigmented ciliary epithelial cells. Several other proteases, including trypsin and plasmin, had little or no effect, of several protease inhibitors tested, only those with specificity for thrombin blocked the effect. Studies with active site-blocked thrombin suggested that the esterolytic active site of thrombin is required for inositol phosphate stimulation, while gamma-thrombin, which has reduced binding affinity to fibrinogen also showed reduced effectiveness in stimulating inositol phosphates. In the presence of 10 mM LiCl, thrombin stimulated inositol monophosphate, inositol bisphosphate and inositol trisphosphate formation, with a prolonged rise of the first and transient early rises in the latter two species. Thrombin also elevated intracellular Ca2+ levels as measured with the fluorescent calcium probe, indo-1-AM. This elevation could be blocked by prior addition to cells of the thrombin inhibitor, hirudin, and was dependent upon extracellular Ca2+ for the maintenance of an elevated level in the presence of thrombin. Incorporation of thymidine into DNA in confluent cultures was also stimulated by thrombin, with a four-fold increase in incorporation at 35 hr in thrombin-treated cells compared to controls. The half-maximal concentration for this process was 0.25 U ml-1. Pretreatment with 100 ng ml-1 pertussis toxin greatly reduced the thrombin effect, which is consistent with a role for a G-protein in stimulation of DNA synthesis by thrombin.

Binding Sites↗
PubMed1991

Binding of inositol phosphates to arrestin.

Arrestin binds to phosphorylated rhodopsin in its light-activated form (metarhodopsin II), blocking thereby its interaction with the G-protein, transducin. In this study, we show that highly phosphorylated forms of inositol compete against the arrestin-rhodopsin interaction. Competition curves and direct binding assays with free arrestin consistently yield affinities in the micromolar range; for example, inositol 1,3,4,5-tetrakisphosphate (InP4) and inositol hexakisphosphate (InP6 bind to arrestin with dissociation constants of 12 microM and 5 microM, respectively. Only a small control amount of inositol phosphates is bound, when arrestin interacts with phosphorylated rhodopsin. This argues for a release of bound inositol phosphates by interaction with rhodopsin. Transducin, rhodopsin kinase, or cyclic GMP phosphodiesterase are not affected by inositol phosphates. These observations open a new way to purify arrestin and to inhibit its interaction with rhodopsin. Their physiological significance deserves further investigation.

Animals↗
PubMed1994

Ca2+ influx evoked by inositol-3,4,5,6-tetrakisphosphate in ras-transformed NIH/3T3 fibroblasts.

Infusion of inositol-3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P4) from the patch pipette into the cytoplasm, produced a biphasic intracellular free Ca2+ concentration ([Ca2+]i) increase in ras-transformed NIH/3T3 (DT) cells. The Ins(3,4,5,6)P4-induced increase in DT cells depended upon extracellular Ca2+, and was enhanced by membrane hyperpolarization. Identical [Ca2+]i increases were observed with intracellular application of inositol-1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) and inositol-1,3,4,6-tetrakisphosphate but not with inositol-1,2,4,5-tetrakisphosphate, inositol-1,4,5-trisphosphate or inositol-1,3,4,5,6-pentakisphosphate. Stimulation of DT cells with bradykinin increased the levels of Ins(3,4,5,6)P4 and Ins(1,3,4,5)P4. These results suggest that Ins(3,4,5,6)P4 may serve as a second messenger for continuous Ca2+ influx along with other tetrakisphosphates downstream from bradykinin receptors in DT cells.

3T3 Cells↗
PubMed1995

Effects of dietary fat supplementation on inositol phosphate release and metabolism in rat left atria.

Eight weeks dietary supplementation with oils enriched in saturated fats, n-6 polyunsaturated fats and n-3 polyunsaturated fats resulted in a reduced inositol phosphate response in isolated rat left atria. Reductions in both basal activity and norepinephrine-stimulated activity were observed. Diets supplemented with n-3 polyunsaturated fats produced a greater decrease in the norepinephrine-stimulated release than the other dietary groups. In addition, supplementation with n-6 polyunsaturated fats resulted in higher levels of the Ca(2+)-releasing compound inositol(1,4,5)trisphosphate while addition of n-3 fats eliminated accumulation of inositol(1, 4)bisphosphate in response to norepinephrine. The reduction in inositol phosphate accumulation observed in all fat-supplemented groups demonstrates the need for caution in choosing relevant control groups in such dietary studies. The specific effects of n-6 and n-3 polyunsaturated fats on individual inositol phosphate isomers demonstrates subtle effects on inositol phosphate metabolism, the significance of which requires further investigation.

Animals↗
PubMed1991

Influence of diabetes on norepinephrine-induced inositol 1,4,5-trisphosphate levels in rat aorta.

The effects of norepinephrine on total tissue levels of inositol 1,4,5-trisphosphate were measured by protein binding assay in aortas from rats with chronic streptozotocin-induced diabetes and from age-matched control rats. In both control and diabetic aortas, norepinephrine induced a rapid, transient and concentration-dependent elevation of inositol 1,4,5-trisphosphate content during contraction. Maximum production of inositol 1,4,5-trisphosphate in response to norepinephrine was greater in diabetic than in control aortas. However, the sensitivities of control and diabetic aortas to norepinephrine for inositol 1,4,5-trisphosphate production were not significantly different. Enhanced norepinephrine-induced production of inositol 1,4,5-trisphosphate in diabetic aortas may contribute to the increased maximum contractile responsiveness of these arteries to the agonist. However, since enhanced contractile responses of diabetic aortas to norepinephrine were also detected at times when inositol 1,4,5-trisphosphate levels were not significantly increased, other factors also appear to be involved in mediating enhanced contractions of diabetic arteries to norepinephrine.

Animals↗
PubMed1993

Reversal of hyperglycemic-induced defects in myo-inositol metabolism and Na+/K+ pump activity in cultured neuroblastoma cells by normalizing glucose levels.

myo-Inositol accumulation and incorporation into phosphoinositides was decreased in neuroblastoma cells chronically exposed to medium containing 30 mmol/L glucose or 30 mmol/L galactose. In addition, the intracellular content of myo-inositol and phosphatidylinositol was decreased and the sorbitol or galactitol content increased in cells cultured for 2 weeks in medium containing 30 mmol/L glucose or 30 mmol/L galactose, respectively. Na+/K+ adenosine triphosphatase (ATPase) transport activity was also significantly decreased by long-term exposure of neuroblastoma cells to medium containing 30 mmol/L glucose or 30 mmol/L galactose. When glucose-conditioned cells were placed in medium containing a normal glucose concentration for 24 hours, myo-inositol metabolism and content, phosphatidylinositol levels, and Na+/K+ pump activity were restored or completely returned to normal values. These functions were also significantly improved, except for the phosphatidylinositol content, which was increased by 55%, when galactose-conditioned cells were incubated for 24 hours in unsupplemented medium. The polyol content of the glucose- or galactose-conditioned cells was also significantly reduced. Returning the cells to normal glucose levels for 1 to 3 hours did not completely restore myo-inositol metabolism. Improved myo-inositol metabolism and content, sorbitol levels, and Na+/K+ ATPase transport activity were also obtained within 24 hours when cells chronically exposed to medium supplemented with 30 mmol/L glucose were placed in medium containing 30 mmol/L glucose and 0.4 mmol/L sorbinil. The phosphatidylinositol content of these cells was improved by approximately 30%. Cells prelabeled for 24 hours with [U-14C]sorbitol metabolize more than 50% of the [U-14C]sorbitol during a 24-hour incubation in unsupplemented medium. These studies conducted at the cellular level suggest that restoration of normal myo-inositol metabolism, polyol content, and Na+/K+ pump activity altered by hyperglycemic conditions occurs rapidly following normalization of glucose concentration.

Animals↗
PubMed1991

The inhibition of agonist- or depolarisation-evoked formation of inositol phosphate by excitatory amino acids in rat cerebral cortex is due to the neurotoxic action of this class of neurotransmitter and is mediated by sodium influx.

Previous work has shown that excitatory amino acids inhibit agonist or depolarisation evoked formation of inositol phosphate in brain. In this paper, possible mechanisms by which this may be occurring have been investigated. The inhibition of carbachol-stimulated formation of inositol phosphate by kainic acid (KA) was abolished if the tissue was incubated in a sodium-free medium. The sodium channel activator, veratridine (10 microM) and the sodium ionophore, monensin (3 microM), also inhibited the response of inositol phosphate to carbachol; tetrodotoxin (300 nM) reversed the effect of veratridine but not monensin or KA. Incubation with cadmium (0.3 mM) or removal of extracellular calcium did not alter the effects of KA, monensin or veratridine. The effects of KA were significantly reduced with the Na+/K(+)-ATPase inhibitor, ouabain (10-100 microM). Inhibition by KA was still observed in tissue that had been prestimulated with KA and then washed to remove the agonist. Incorporation of [3H]inositol into inositol lipids was significantly reduced by KA, in the absence or presence of carbachol. It is suggested that the inhibition of the turnover of stimulated phosphoinositide, by excitatory amino acids, is related to the neurotoxic actions of these transmitters and is mediated by Na+ influx, with a consequent activation of Na+/K(+)-ATPase, depletion of cellular ATP and reduction in synthesis of inositol lipid.

Animals↗
PubMed1987

Biochemical aspects of the phosphoinositide signalling system with special reference to the formation of inositol cyclic phosphates and arachidonic acid and metabolites on agonist stimulation.

Several aspects of the phosphoinositide signalling system recently studied in our Laboratory are considered here. 1. The formation of inositol 1:2-cyclic-4,5-trisphosphate (IcP3) and inositol 1:2-cyclic-4-bisphosphate (IcP2) have been shown here to occur in pancreatic minilobules stimulated with carbamylcholine. Identification is based on mobility on ionophoresis on paper and on HPLC, acid lability, and conversion of the inositol cyclic phosphates to their respective non-cyclic inositol phosphates on treatment with acid. The levels of inositol 1:2-cyclic phosphate (IcP), IcP2, and IcP3 were 0.7%, 6.8%, and 29.8% of their respective non-cyclic inositol phosphates. The level of IcP3 is sufficient to evoke release of calcium from the endoplasmic reticulum. 2. In a previous study, we demonstrated that on agonist stimulation of pancreatic minilobules prelabelled with [14C]arachidonate, [14C]stearate, or [3H]glycerol, there was a substantial release of all three of these compounds, amounting to approximately 50% of the total PI loss, which was up to 70% of the total cellular PI (7). It was shown that this loss in PI was due to the sequential actions of phospholipase C and diacylglycerol (DG) lipase. Evidence against the phospholipase A2 pathway was no formation of lysophosphatidylinositol. Further evidence against the phospholipase A2 pathway shown here is the lack of stimulation by agonist of glycerophosphorylinositol formation. We also show here that the stimulation of PI loss in guinea pig brain cortex slices is likely also to be via the sequential actions of phospholipase C and DG-lipase, i.e., there was an increase in the steady-state level of monoacylglycerol and a rise in free arachidonate on stimulation with acetylcholine. The formation of prostaglandin E and prostaglandin F was also increased in brain cortex, corpus striatum, and hippocampus. The effects of acetylcholine were abolished by atropine. 3. Previous studies showed that the DG-lipase inhibitor, RHC 80267, inhibited agonist-stimulated formation of glycerol and fatty acids and raised the steady-state level of DG (7). We have now used RHC 80267 as a tool to elevate the level of DG and to lower the level of arachidonate to see if either of these products might modulate the carbamylcholine-stimulated cGMP levels in pancreatic minilobules. RHC 80267 inhibited formation of cGMP. Addition of arachidonate did not affect this inhibition, nor did addition of free arachidonate to control minilobules have any effect, thus suggesting that liberation of free arachidonate by carbamylcholine was not responsible for the carbamylcholine-induced rise in cGMP.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗