SEARCH · Search PubMed

Results for “Inositol Phosphates”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources

PubMed1990

Agonist-stimulated inositol phosphate metabolism in avian erythrocytes.

1. A screen for agonists capable of stimulating the formation of inositol phosphates in erythrocytes from 5-day-old chickens revealed the presence of a population of phosphoinositidase C-linked purinergic receptors. 2. If chicken erythrocytes prelabelled with [3H]Ins were exposed to a maximal effective dose of adenosine 5'-[beta-thio]diphosphate for 30 s, the agonist-stimulated increment in total [3H]inositol phosphates was confined to [3H]Ins(1,4,5)P3, Ins(1,3,4,5)P4 and InsP2. After 40 min stimulation, the radiolabelling of nearly all of the [3H]inositol phosphates that have been detected in these extracts [Stephens, Hawkins & Downes (1989) Biochem. J. 262, 727-737] had risen. However, some of these increases [especially those in Ins(3,4,5,6)P4 and Ins(1,3,4,5,6)P5] were accountable for almost entirely by increases in specific radioactivity rather than in mass. 3. The effect of purinergic stimulation on the rate of incorporation of [32P]Pi in the medium into the gamma-phosphate group of ATP and InsP4 and InsP5 was also measured. After 40 min stimulation, the incorporation of 32P into Ins(1,3,4,6)P4, Ins(1,3,4,5)P4, Ins(3,4,5,6)P4 and Ins(1,3,4,5,6)P5 was significantly elevated, whereas the mass of the last two and the specific radioactivity of the gamma-phosphate of ATP were unchanged compared with control erythrocyte suspensions. 4. In control suspensions of avian erythrocytes, the specific radioactivity of the individual phosphate moieties of Ins(1,3,4,6)P4 increased through the series 1, 6, 4 and 3 [Stephens & Downes (1990) Biochem. J. 265, 435-452]. This pattern of 32P incorporation is not the anticipated outcome of 6-hydroxy phosphorylation of Ins(1,3,4)P3 [the assumed route of synthesis of Ins(1,3,4,6)P4]. Although adenosine [beta-thio]diphosphate significantly stimulated the accumulation of [3H]Ins(1,3,4)P3, and despite the fact that avian erythrocyte lysates were shown to possess a chromatographically distinct, soluble, ATP-dependent, Ins(1,3,4)P3 6-hydroxykinase activity, purinergic stimulation of intact cells did not significantly alter the pattern of incorporation of [32P]Pi into the individual phosphate moieties of Ins(1,3,4,6)P4. These results suggest that the route of synthesis of this inositol phosphate species is not changed during the presence of an agonist.

Adenosine Diphosphate↗

PubMed1988

Evidence that angiotensin II is a paracrine agent mediating gonadotrophin-releasing hormone-stimulated inositol phosphate production and prolactin secretion in the rat.

Gonadotrophin-releasing hormone (GnRH) stimulated the accumulation of inositol phosphates and prolactin secretion in anterior pituitary cells from young male rats. Saralasin [( Sar1, Ala8]-angiotensin II; a competitive antagonist of angiotensin II) inhibited the increase in both inositol phosphates and prolactin in a dose-dependent manner. Since angiotensin II has been shown to be a potent stimulus for inositol phosphate accumulation and prolactin secretion in the lactotroph, these findings suggest that angiotensin II acts as a paracrine agent, being released from the gonadotroph in response to GnRH and causing the lactotroph to release prolactin through an effect on phosphoinositide metabolism. The ability of GnRH to promote prolactin release was lost in pituitaries from older rats, and the increase in total inositol phosphate accumulation was less. These findings provide evidence of a physiological role for the presence of the renin-angiotensin system within the pituitary gland.

Angiotensin II↗

PubMed1988

Regulation of epidermal growth factor-stimulated formation of inositol phosphates in A-431 cells by calcium and protein kinase C.

Epidermal growth factor (EGF) treatment of A-431 cells induces a biphasic increase in the levels of inositol phosphates. The growth factor produces an initial, rapid increase in the level of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) due to hydrolysis of phosphatidyl-inositol-4,5-bisphosphate (Wahl, M., Sweatt, J. D., and Carpenter, G. (1987) Biochem. Biophys. Res. Commun. 142, 688-695). The level of inositol 1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4) also rises rapidly in response to treatment with EGF. The initial formation (less than 1 min) of Ins-1,4,5-P3 and Ins-1,3,4,5-P4 does not require Ca2+ present in the culture medium. However, the addition of Ca2+ to the medium at levels of 100 microM or greater potentiates the growth factor-stimulated increases in the levels of all inositol phosphates at later times after EGF addition (1-60 min). The data suggest that EGF-receptor complexes initially stimulate the enzyme phospholipase C in a manner that is independent of an influx of extracellular Ca2+. The presence of Ca2+ in the medium allows prolonged growth factor activation of phospholipase C. Treatment of A-431 cells with Ca2+ ionophores (A23187 and ionomycin) did not mimic the activity of EGF in producing a rapid increase in the formation of the Dowex column fraction containing Ins-1,4,5-P3, Ins-1,3,4,5-P4, and inositol 1,3,4-trisphosphate (InsP3). However, the initial EGF-stimulated formation of inositol phosphates was substantially diminished in cells loaded with the Ca2+ chelator Quin 2/AM. EGF receptor occupancy studies indicated that maximal stimulation of InsP3 accumulation by EGF requires nearly full (75%) occupancy of available EGF binding sites, while half-maximal stimulation requires 25% occupancy. 12-O-Tetradecanoylphorbol-13-acetate (TPA), an exogenous activator of Ca2+/phospholipid-dependent protein kinase (protein kinase C), causes a dramatic, but transient, inhibition of the EGF-stimulated formation of inositol phosphates. Tamoxifen and sphingosine, reported pharmacologic inhibitors of protein kinase C activity, potentiate the capacity of EGF to induce formation of inositol phosphates. Neither TPA nor tamoxifen significantly affects the 125I-EGF binding capacity of A-431 cells; however, TPA appeared to enhance internalization of the ligand. Ligand occupation of the EGF receptor on the A-431 cell appears to initiate a complex signaling mechanism involving production of intracellular messengers for Ca2+ mobilization and activation of protein kinase C.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

5-HT1C receptor-mediated stimulation of inositol phosphate production in pig choroid plexus. A pharmacological characterization.

1) 5-HT (5-hydroxytryptamine, serotonin) induces inositol phosphate production in a pig choroid plexus preparation. This effect has been pharmacologically characterized and the data compared to those obtained from radioligand binding studies performed with [3H]mesulergine to 5-HT1C sites in pig choroid plexus membranes. 2) The rank order of potency of agonists stimulating inositol phosphate production was: alpha-methyl-5-HT greater than 1-methyl-5-HT greater than DOI greater than bufotenine = SKF 83566 = 5-HT greater than 5-MeO-DMT greater than 5-MeOT = RU 24969 greater than SCH 23390 greater than 5-CT. 8-OH-DPAT was virtually devoid of activity at 100 mumol/l. 3) The increase in inositol phosphate production induced by 5-HT and other agonists was surmountably antagonised by mesulergine, ketanserin and spiperone with pKB values of 8.7, 6.7 and 5.3, respectively. 4) The rank order of potency of antagonists was: metergoline greater than mesulergine greater than LY 53857 greater than ritanserin greater than methiothepin greater than mianserin greater than cyproheptadine greater than pirenperone greater than cinanserin greater than ketanserin greater than spiperone. The following antagonists were virtually devoid of activity at 100 mumol/l; pindolol, 21-009 and yohimbine. 5) The results obtained both with agonists and antagonists strongly support the view that 5-HT1C receptors mediate agonist induced production of inositol phosphates in pig choroid plexus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Heteromeric, but not homomeric, connexin channels are selectively permeable to inositol phosphates.

Previous work has shown that channels formed by both connexin (Cx)26 and Cx32 (heteromeric Cx26/Cx32 hemichannels) are selectively permeable to cAMP and cGMP. To further investigate differential connexin channel permeability among second messengers, and the influence of connexin channel composition on the selectivity, the permeability of inositol phosphates with one to four phosphate groups through homomeric Cx26, homomeric Cx32, and heteromeric Cx26/Cx32 channels was examined. Connexin channels were purified from transfected HeLa cells and from rat, mouse, and guinea pig livers, resulting in channels with a broad range of Cx26/Cx32 aggregate ratios. Permeability to inositol phosphates was assessed by flux through reconstituted channels. Surprisingly, myoinositol and all inositol phosphates tested were permeable through homomeric Cx32 and homomeric Cx26 channels. Even more surprising, heteromeric Cx26/Cx32 channels showed striking differences in permeability among inositol phosphates with three or four phosphate groups and among isomers of inositol triphosphate. Thus, heteromeric channels are selectively permeable among inositol phosphates, whereas the corresponding homomeric channels are not. There was no discernible difference in the permeability of channels with similar Cx26/Cx32 ratios purified from native and heterologous sources. The molecular selectivity of heteromeric channels among three inositol triphosphates could not be accounted for by simple connexin isoform stoichiometry distributions and therefore may depend on specific isoform radial arrangements within the hexameric channels. Dynamic regulation of channel composition in vivo may effectively and efficiently modulate intercellular signaling by inositol phosphates.

Animals↗

PubMed1993

Alpha 1A and alpha 1B-adrenoceptors enhance inositol phosphate generation in rat renal cortex.

We have studied the role of alpha 1A- and alpha 1B-adrenoceptors in noradrenaline- and methoxamine-stimulated inositol phosphate accumulation in rat renal cortical slices. [3H]Prazosin binding studies with and without inactivation of alpha 1B-adrenoceptors by chloroethylclonidine treatment suggested that noradrenaline lacks relevant selectivity for alpha 1-adrenoceptor subtypes. Both agonists stimulated [3H]inositol phosphate accumulation with similar maximal effects. The alpha 1A-selective antagonists 5-methyl-urapidil and (+)-niguldipine inhibited inositol phosphate formation by both agonists with shallow biphasic curves but the high affinity component was only 15%-31% and 38%-41%, respectively. The irreversible alpha 1B-selective antagonist chloroethylclonidine inhibited inositol phosphate generation by both agonists by 54%-57%. In contrast to our previous data in rat cerebral cortical slices, we conclude that in rat renal cortex both alpha 1A- and alpha 1B-adrenoceptors are involved in noradrenaline- and methoxamine-stimulated inositol phosphate generation.

Adrenergic alpha-Antagonists↗

PubMed1990

Dual mechanisms of inhibition by dopamine of basal and thyrotropin-releasing hormone-stimulated inositol phosphate production in anterior pituitary cells. Evidence for an inhibition not mediated by voltage-dependent Ca2+ channels.

In primary cultures of anterior pituitary cells, dopamine inhibited basal and thyrotropin-releasing hormone (TRH)-stimulated inositol monophosphate, bisphosphate, and trisphosphate production. This inhibition by dopamine can be resolved into two distinct components. One of the components was rapid and already present after 10 s. The other was slower, starting after 1 min, and was mimicked by nimodipine, a dihydropyridine calcium channel antagonist. The effects of dopamine and nimodipine were not additive on both basal and TRH-stimulated inositol phosphate production. Furthermore, the dopamine inhibition in the presence of TRH was much higher than the inhibition induced by nimodipine. It is thus likely that calcium entry through voltage-dependent calcium channels triggers a positive feedback on TRH stimulation of phospholipase C. However, depolarizing concentrations of K+ or BAY-K-8644, a voltage-dependent calcium channel agonist, had no effect on inositol monophosphate and bisphosphate accumulation. Ionomycin, even at a very high concentration (10 microM), had only a slight and transient effect on inositol phosphate formation. In addition, these agents did not affect the TRH dose-dependent stimulation of inositol phosphate production. These results suggest that the intracellular calcium concentrations that we measured under basal and TRH-stimulated conditions are sufficient to allow the maximal activity of phospholipase C which can be obtained under these two experimental conditions. In contrast, any decrease in the intracellular calcium concentration by a dihydropyridine antagonist, suppression of extracellular calcium, or inactivation of a voltage-dependent calcium channel by long term depolarization with K+ decreased the phospholipase C activities measured under basal and TRH-stimulated conditions. From these data it can be concluded that dopamine inhibits inositol phosphate production by two distinct mechanisms. The slow dopamine-induced inhibition of TRH-stimulated inositol phosphate production which is mimicked by nimodipine is likely because of an inhibition of a voltage-dependent calcium channel. This is substantiated further by the fact that ionomycin (10 microM) was able to reverse the nimodipine inhibitions as well as this slow component of dopamine inhibition. The nature of the rapid inhibition of TRH-stimulated inositol phosphate production induced by dopamine, but not by nimodipine, remains to be determined. It is suppressed in the absence of extracellular Ca2+. This may suggest that this inhibition is related to blockade of non-dihydropyridine-sensitive Ca2+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)

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

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↗

PubMed1991

Histamine H1 receptor occupancy triggers inositol phosphates and intracellular calcium mobilization in human non-pigmented ciliary epithelial cells.

Agonists and antagonists of histamine were used to characterize the stimulation of inositol phosphates formation and elevation of intracellular Ca2+ by histamine in cultured non-pigmented epithelial (NPE) cells from human ciliary body. Agonists specific for the H1 histamine receptor subtype were 20- to 200-fold more potent than the H2-specific agonists tested, and 5-16% as potent as histamine in inositol phosphates stimulation. An H1 antagonist was 10,000-fold more potent than an H2 antagonist in blocking histamine stimulation of inositol phosphates. H1 agonists also mimicked and H1 antagonists inhibited the elevation of intracellular Ca2+ by histamine. The first phase of the Ca2+ response to histamine was largely independent of extracellular Ca2+ while the second phase required extracellular Ca2+. Dose-response curves for histamine elevation of intracellular Ca2+ (EC50 = 10 microM, maximum at 100 microM) and inositol phosphates (EC50 = 2 microM, maximum at 100 microM) were similar. These data support the characterization of the NPE histamine receptor as an H1 receptor linked to elevation of inositol phosphates and intracellular Ca2+.

Calcium↗

PubMed1987

Inositol phosphates accumulation in ovarian granulosa after stimulation by luteinizing hormone.

Accumulation of inositol phosphates by granulosa cells from medium follicles of porcine ovaries was studied to determine if hydrolysis of phosphoinositides is stimulated by luteinizing hormone (LH). Although follicle-stimulating hormone (FSH), D-alanine-gonadotropin-releasing hormone (D-ala-GnRH), and dibutyryl cyclic adenosine 3',5'-monophosphate (dbcAMP) had no effect, LH increased accumulation of inositol phosphate (IP), -bisphosphate (IP2), and trisphosphate (IP3) by severalfold. Furthermore, 0.01 microgram LH/ml increased IP3 accumulation threefold, while 0.1 microgram/ml stimulated accumulation of all inositol phosphates. Compared to untreated cells, LH-treated granulosa cells produced approximately twice as much progesterone in 30 min. Preincubation of cells with lithium chloride (LiCl) was necessary to measure IP accumulation, but not IP2 and IP3 accumulations. However, IP2 and IP3 accumulations were higher in LH-treated granulosa after pretreatment with LiCl. Maximal increases in IP3 and IP2 accumulations occurred approximately 15 min and 30 min, respectively, after LH stimulation, whereas the effect of LH on IP accumulation continued for at least 60 min. Granulosa, made permeable to IP3 with saponin treatment, did not hydrolyze [3H]IP3 to [3H]IP2 or [3H]IP. Thus, it is hypothesized that LH stimulates phosphoinositide hydrolysis in granulosa cells, thereby generating putative second messengers.

Animals↗

PubMed1993

Inositol phosphates in rat atria and the importance of the extraction procedure.

The nature of the inositol phosphates present in adult rat left atria have been examined. Trichloroacetic acid extracts of [3H] inositol-labelled left atria contained the 1 (or 3)-, 2- and 4-isomers of inositol monophosphate, inositol-1,4-bisphosphate, and inositol-1,4,5-trisphosphate. Addition of noradrenaline increased all of these isomers. However, even in the presence of noradrenaline, there was no evidence for the presence of inositol-1,3,4,5-tetrakisphosphate or its dephosphorylation products including inositol-1,3,4-trisphosphate and the 1,3- and 3,4-isomers of inositol bisphosphate. Total accumulation of inositol phosphates in the presence of LiCl was 98% accounted for by dephosphorylation of inositol-1,4,5-trisphosphate and its cyclic isomer. These data indicate that, in intact left atria, metabolism of inositol-1,4,5-trisphosphate is by dephosphorylation and that significant activity of the phosphorylation pathway is not present. When extractions were performed using either acidified chloroform-methanol or perchloric acid, other [3H] inositol-labelled compounds were detected in atrial extracts. One of these chromatographed with ATP and might be mistaken for inositol-1,3,4-trisphosphate if co-chromatography with ATP was used to identify that compound. Another compound had a similar, but not identical chromatographic profile to inositol-1,3,4,5-tetrakisphosphate and is thus likely to be mistaken for that compound. In addition, perchloric acid extraction caused phosphate group migration generating extra isomers of the inositol phosphates and other unidentified [3H]-labelled compounds. Such extraction artifacts are likely especially problematic in studies of intact heart tissue because of the time required to effectively homogenize the tissue. These findings demonstrate the need for caution in interpreting data relating to estimations of inositol phosphates in intact heart tissue.

Animals↗

PubMed1997

Studies of inositol phosphate export from neuronal tissue in vitro.

Recent in vivo microdialysis studies have demonstrated the presence of extracellular levels of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] that can be increased in a concentration-dependent manner by muscarinic receptor activation. The aim of the present study was to determine whether extracellular levels of Ins(1,4,5)P3 could be measured in vitro. Despite rapid increases in internal Ins(1,4,5)P3 levels after stimulation with 1 mM carbachol, there was no change in external levels in both rat brain cortical slices and human neuroblastoma SH-SY5Y cells. Suprafusion of myo-[3H]inositol-prelabelled hippocampal slices with 1 mM carbachol caused an increase in 3H-inositol phosphates over basal levels in the perfusate after 10 min, reaching a peak (223 +/- 56% of basal) 20 min after suprafusion with carbachol was started. This response to carbachol was potentiated in the presence of 30 mM K+. Analysis of the individual 3H-inositol phosphates in the perfusate revealed that levels of [3H]inositol monophosphate, [3H]inositol bisphosphate, [3H]inositol trisphosphate, and [3H]inositol tetrakisphosphate were all significantly increased. A similar increase in extracellular 3H-inositol phosphates was demonstrated in SH-SY5Y cells incubated with 1 mM carbachol for 30 min. This response was again enhanced by 30 mM K+, although the intracellular response was not potentiated. Possible roles for extracellular inositol phosphates are discussed.

Animals↗

PubMed1996

Defective calcium increase and inositol phosphate production in anti-CD3-stimulated lymphocytes of alcoholics without progressive liver disease.

Intracellular free calcium concentration, phosphoinositide turnover, and inositol phosphate production were analyzed in peripheral blood lymphocytes from seven well-nourished alcoholic patients without severe acute or chronic liver disease, before and after stimulation with anti-CD3 antibody. Seven comparable nondrinkers were studied as controls. A lower increase in intracellular free calcium concentration was detected in alcoholics, after anti-CD3 stimulation of lymphocytes, than in control subjects. Lymphocyte activation generated inositol phosphates in both controls and alcoholics, but inositol phosphate production was significantly lower in alcoholics. The agreement between these findings indicates that the reduction in inositol phosphates is one of the most important events in the early phases of lymphocyte activation in alcoholics.

Adult↗

PubMed1997

Analysis of inositol phosphates in heart tissue using anion-exchange high-performance liquid chromatography.

The pathways of release and metabolism of inositol phosphates in intact heart tissue are different from those observed in isolated cardiomyocytes in culture. Thus, it is essential that methods are available for the quantitation of inositol phosphates in intact tissue preparations. This manuscript describes methods which allow the quantitation of inositol phosphates in different heart preparations including isolated atria and intact perfused heart. The availability of such methods should facilitate study of the role of inositol phosphates in cardiac control mechanisms under physiological and pathological conditions.

Animals↗

PubMed2003

Scintillation proximity assay of inositol phosphates in cell extracts: high-throughput measurement of G-protein-coupled receptor activation.

The phosphatidylinositol turnover assay is used widely to measure activation, and inhibition, of G(q)-linked G-protein-coupled receptors. Cells expressing the receptor of interest are labeled by feeding with tritiated myo-inositol. The label is incorporated into cellular phosphatidylinositol 4,5-bisphosphate, which, upon agonist binding to the receptor, is hydrolyzed by phospholipase C to inositol 1,4,5-trisphosphate (IP(3)) and diacylglycerol. In the presence of Li(+), dephosphorylation of IP(3) to inositol is blocked, and the mass of soluble inositol phosphates is a quantitative readout of receptor activation. Current protocols for this assay all involve an anion-exchange chromatography step to separate radiolabeled inositol phosphates from radiolabeled inositol, making the assay cumbersome and difficult to automate. We now describe a scintillation proximity assay to measure soluble inositol phosphate mass in cell extracts, thus obviating the need for the standard chromatography step. The method uses positively charged yttrium silicate beads that bind inositol phosphates, but not inositol. We have used this assay to measure activation of recombinant and endogenous muscarinic acetylcholine receptors and activation of recombinant neuropeptide FF2 receptor coupled to IP(3) production by coexpression of a chimeric G protein. Further, we demonstrate the use and functional validity of this assay in a semiautomated, 384-well format, by characterizing the muscarinic receptor antagonists pirenzepine and atropine.

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↗

PubMed1998

Adenosine A1 receptor activation inhibits basal accumulation of inositol phosphates in rat hippocampus.

The ability of the adenosine A1 receptor selective agonist, N6-cyclopentyladenosine, to modify basal accumulation of inositol phosphates in rat hippocampal slices, was investigated. Cyclopentyladenosine (10-300 nM) inhibited the basal accumulation of total [3H]inositol phosphates, with an EC50 of 10 nM and an Emax of 24%. This effect of cyclopentyladenosine was prevented by the adenosine A1 receptor selective antagonist, 1,3-dipropyl-8-cyclopentylxanthine (30 nM). Cyclopentyladenosine (100 nM) also inhibited histamine (300 nM)-stimulated accumulation of [3H]inositol phosphates, this effect being quantitatively similar to that observed on basal [3H]inositol phosphates accumulation. The results suggest that adenosine A1 receptor activation is able, per se, to inhibit the formation of phosphatidylinositol-derived second messengers in hippocampus.

Adenosine↗

PubMed1988

Inhibition of inositol phosphate production is a late, Ca2+-dependent effect of D2 dopaminergic receptor activation in rat lactotroph cells.

The effect of dopamine, working through the activation of D2 receptors, on inositol phosphate production induced by thyrotropin-releasing hormone (TRH) was investigated in rat pituitary lactotroph cells. Dopamine (10 microM) did not modify the initial rapid stimulation of inositol 1,4,5-triphosphate and inositol bisphosphate observed within the first 15 s after TRH addition, but progressively inhibited the later inositol phosphate production induced by the neurohormone. This kinetics of inhibition was independent of dopamine preincubation time (from 2 to 10 min). The effect was still visible when dopamine was added after TRH. It was sensitive to pertussis toxin, was unchanged by increasing cellular cAMP levels with 8-Br-cAMP, but was greatly affected by treatments that modify the cytosolic free Ca2+ concentration. Specifically, the dopamine-induced inhibition was prevented by treatment of the cells with the Ca2+ ionophore ionomycin (100-200 nM) and was mimicked either by withdrawal of Ca2+ from the incubation medium or by blockade of voltage-gated Ca2+ channels with verapamil. The dopamine treatment did not decrease the cellular levels of the various phosphoinositides, strongly suggesting that the inhibition of inositol phosphate production is not due to precursor depletion. In isolated membranes, however, dopamine was unable to counteract the inositol phosphate accumulation triggered by TRH. Taken together, the data indicate that inhibition of inositol phosphate production is not a primary event triggered by D2 receptor activation, but is a late consequence, due to the previously demonstrated (Malgaroli, A., Vallar, L., Reza Elahi, F., Pozzan, T., Spada, A., and Meldolesi, J. (1987) J. Biol. Chem. 262, 13920-13927) inhibition by dopamine of the prolonged cytosolic free Ca2+ concentration increase induced by TRH via the activation of voltage-gated Ca2+ channels. These results are inconsistent with the possibility of a direct inhibitory coupling of D2 receptors to phospholipase C in rat pituitary lactotroph cells.

8-Bromo Cyclic Adenosine Monophosphate↗