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PubMed1989

Tumor promoter 12-O-tetradecanoylphorbol 13-acetate inhibits mas/angiotensin receptor-stimulated inositol phosphate production and intracellular Ca2+ elevation in the 401L-C3 neuronal cell line.

Stimulation of mas-oncogene transfected 401L-C3 cells by angiotensins leads to the production of inositol phosphates. This response shows dose dependence, and has an apparent rank order of potency angiotensin III greater than or equal to angiotensin II much greater than angiotensin I. Preincubation with 12-O-tetradecanoylphorbol 13-acetate, for 5 min, significantly diminishes both inositol phosphate and intracellular [Ca2+] responses to angiotensins, without affecting those stimulated by the endogenous bradykinin receptor. Incubation of 401L-C3 cells with either phorbol ester or angiotensins leads to elevation of intracellular pH, implying that mas/angiotensin receptor stimulation itself leads to protein kinase C activation. These results suggest the operation of a negative feedback loop specific for the mas/angiotensin receptor signalling pathway, and which may be essential in defining the final biological output response to this receptor stimulation.

Angiotensin I↗
PubMed1994

Effects of histamine on inositol phosphates and intracellular Ca2+ in human glomerular epithelial cells.

The effect of histamine on the phosphoinositide turnover and intracellular free calcium activity [Ca2+]i was examined in human glomerular epithelial cells in culture. Addition of histamine to glomerular epithelial cells resulted in formation of inositol phosphates in a time- and dose-dependent manner. A transient maximum of inositol trisphosphate (InsP3) was observed within 10 s. Stimulation of protein kinase C by short-term pretreatment (15 min) of glomerular epithelial cells with phorbol 12-myristate 13-acetate caused a dose-dependent inhibition of the histamine-induced inositol phosphate accumulation. The baseline of [Ca2+]i in the cells was 115 +/- 2.7 nmol/l (n = 103). Histamine (ED50: approx. 2 x 10(-7) mol/l) caused a rapid and transient increase in [Ca2+]i as detected by fura-2 microfluorimetry studies. In a calcium-free extracellular solution the rapid increase of [Ca2+]i was still present. The H1 receptor antagonist mepyramine (IC50: approx. 8 x 10(-9) mol/l) inhibited the histamine (10(-6) mol/l) response on [Ca2+]i. Cimetidine, a potent H2 receptor antagonist, showed no effect. This data indicates that H1 receptor activation causes hydrolysis of phosphatidylinositol 4, 5-bisphosphate by phospholipase C activation, and consecutive mobilization of intracellular calcium. Since histamine is a mediator of inflammation, antigen response and cellular injury, these findings could be of importance for the understanding of glomerular epithelial cell pathology.

Calcium↗
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↗
PubMed2005

An anionic inositol phosphate glycan pseudotetrasaccharide exhibits high insulin-mimetic activity in rat adipocytes.

Inositol phosphate glycan pseudotetrasaccharides consisting of man-(alpha1-6)-man-(alpha1-4)-glcN-(alpha,beta1-6)-myo-inositol-1,2-cyclic phosphate possessing a sulfate group at either O-6 (compounds 3alpha,beta) or O-2 (compounds 4alpha,beta) of the terminal mannose have been prepared. Compound 4alpha was able to stimulate lipogenesis in native rat adipocytes to 78% of the maximal insulin response (MIR) with an EC50 of 1.1 microM. The other compounds exhibited lower maximal stimulations (47-63% MIR) and higher EC50 values (9.5-10.6 microM).

Adipocytes↗
PubMed1995

Pertussis toxin sensitive endothelin-1 coupling to inositol phosphate formation via a GTP-binding protein: comparison in SHR and WKY cultured aortic smooth muscle cells.

The effects of pertussis toxin on endothelin-1 and noradrenaline coupling to inositol phosphate (IP) formation was investigated in cultured aortic smooth muscle cells from 14 week SHR and WKY rats. Endothelin-1 (10(-6) M) stimulated IP formation was decreased in cells from SHR compared to WKY (WKY 1117 +/- 157, SHR 668 +/- 85% of basal). Pre-incubation with pertussis toxin produced a significant and similar reduction in endothelin stimulated IP production in both SHR (54% reduction) and WKY (55%). However, the observed reduction in endothelin-1 stimulated IP accumulation was still apparent in SHR when compared to WKY. Pertussis toxin preincubation followed by removal of extracellular calcium reduced further the endothelin responses by similar amounts in SHR and WKY cells, but SHR stimulated IP formation remained significantly decreased compared to WKY. The extent of pertussis toxin ADP-ribosylation of Gi alpha was similar in both SHR and WKY cells. Endothelin-1 produced a reduction in the extent of ADP-ribosylation of Gi alpha and this was of similar magnitude in both SHR and WKY cell membranes. In contrast, noradrenaline stimulated IP formation was unaffected by pertussis toxin pre-incubation. It was concluded that SHR cells do not appear to have an alteration in endothelin-1 activated, pertussis toxin sensitive G-protein coupling to IP formation or in the dependence of inositol phosphate formation on extracellular calcium.

Animals↗
PubMed1998

SopB, a protein required for virulence of Salmonella dublin, is an inositol phosphate phosphatase.

Several proteins secreted by enteric bacteria are thought to contribute to virulence by disturbing the signal transduction of infected cells. Here, we report that SopB, a protein secreted by Salmonella dublin, has sequence homology to mammalian inositol polyphosphate 4-phosphatases and that recombinant SopB has inositol phosphate phosphatase activity in vitro. SopB hydrolyzes phosphatidylinositol 3,4,5-trisphosphate, an inhibitor of Ca2+-dependent chloride secretion. In addition, SopB hydrolyzes inositol 1,3,4,5,6 pentakisphosphate to yield inositol 1,4,5, 6-tetrakisphosphate, a signaling molecule that increases chloride secretion indirectly by antagonizing the inhibition of chloride secretion by phosphatidylinositol 3,4,5-trisphosphate [Eckmann, L., Rudolf, M. T., Ptasznik, A., Schultz, C., Jiang, T., Wolfson, N., Tsien, R., Fierer, J., Shears, S. B., Kagnoff, M. F., et al. (1997) Proc. Natl. Acad. Sci. USA 94, 14456-14460]. Mutation of a conserved cysteine that abolishes phosphatase activity of SopB results in a mutant strain, S. dublin SB c/s, with decreased ability to induce fluid secretion in infected calf intestine loops. Moreover, HeLa cells infected with S. dublin SB c/s do not accumulate high levels of inositol 1,4,5,6-tetrakisphosphate that are characteristic of wild-type S. dublin-infected cells. Therefore, SopB mediates virulence by interdicting inositol phosphate signaling pathways.

Amino Acid Sequence↗
PubMed1995

Control of inositol phosphate turnover in human airways during histamine stimulation.

The control of inositol phosphate (IP) turnover was investigated in intact human airway smooth muscle cells (SMC) during a brief exposure to a bronchoconstrictor agonist. The pool of membrane phosphatidylinositol 4,5-biphosphate was labelled by incubating SMC with myo-[3H]inositol and the [3H]IPs synthetized ([3H]1,4-IP2, [3H]1,3,4,-IP3, [3H]1,4,5,-IP3 and [3H]1,3,4,5-IP4) were separated by HPLC. We examined the role of protein kinase C (PKC) and of Ca2+ on IP turnover during a 5 sec application of histamine. Activation of PKC with the phorbol ester PMA (0.2 microM) decreased, whereas inhibition of PKC with 1 microM staurosporine increased the production of the 4 IPs examined in unstimulated and in histamine-stimulated SMC. Decreasing [Ca2+]i with 5 microM ionomycin in the absence of external Ca2+ diminished the IP production whereas in the presence of Ca2+, ionomycin exalted it and potentiated the response to histamine. Thapsigargin, 5 microM, which depletes the 1,4,5-IP3-sensitive Ca2+ stores, reduced the IP production due to histamine. The effects of PMA, staurosporine and thapsigargin were also tested on [Ca2+]i in fura-2-loaded single SMC. These results reveal that PKC exerts a negative and Ca2+ a positive feedback control on phospholipase C, that operate within 5 sec of agonist stimulation.

Alkaloids↗
PubMed1990

Early induction of ornithine decarboxylase occurs simultaneously with inositol phosphate accumulation in concanavalin A-stimulated rat thymocytes.

Stimulation of rat thymocytes with the lectin ConA produced an early peak of ornithine decarboxylase (ODC) activity within 10 min. This ODC induction appeared as early as the well-known inositol phosphate accumulation following mitogenic stimulation, and may be part of the signal transduction mechanism. The distribution of counts among the inositol phosphates was constant during the overall time of Concanavalin A (ConA) stimulation. We conclude that early induction of pre-existing ODC may be independent of protein kinase C action.

Animals↗
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↗
PubMed1988

Regulation of GH3-cell function via adenosine A1 receptors. Inhibition of prolactin release, cyclic AMP production and inositol phosphate generation.

We examined the mechanism by which adenosine inhibits prolactin secretion from GH3 cells, a rat pituitary tumour line. Prolactin release is enhanced by vasoactive intestinal peptide (VIP), which increases cyclic AMP, and by thyrotropin-releasing hormone (TRH), which increases inositol phosphates (IPx). Analogues of adenosine decreased prolactin release, VIP-stimulated cyclic AMP accumulation and TRH-stimulated inositol phospholipid hydrolysis and IPx generation. Inhibition of InsP3 production by R-N6-phenylisopropyladenosine (R-PIA) was rapid (15 s) and was not affected by the addition of forskolin or the removal of external Ca2+. Addition of adenosine deaminase or the potent adenosine-receptor antagonist, BW-A1433U, enhanced the accumulation of cyclic AMP by VIP, indicating that endogenously produced adenosine tonically inhibits adenylate cyclase. The potency order of adenosine analogues for inhibition of cyclic AMP and IPx responses (measured in the presence of adenosine deaminase) was N6-cyclopentyladenosine greater than R-PIA greater than 5'-N-ethylcarboxamidoadenosine. This rank order indicates that inhibitions of both cyclic AMP and InsP3 production are mediated by adenosine A1 receptors. Responses to R-PIA were blocked by BW-A1433U (1 microM) or by pretreatment of cells with pertussis toxin. A greater amount of toxin was required to eliminate the effect of R-PIA on inositol phosphate than on cyclic AMP accumulation. These data indicate that adenosine, in addition to inhibiting cyclic AMP accumulation, decreases IPx production in GH3 cells, possibly by directly inhibiting phosphoinositide hydrolysis.

Adenosine↗
PubMed1988

Dopamine D2 receptor stimulation inhibits inositol phosphate generating system in rat striatal slices.

Previous studies on the transduction mechanisms triggered by dopamine receptor stimulation have established that both D1 and D2 subtypes of dopamine receptors are linked to the adenylate cyclase system, the former in a stimulatory and the latter in an inhibitory manner. The present report provides the first evidence that stimulation of D2 receptors in rat brain tissue affects the turnover of polyphosphoinositides, as revealed by changes of the content of inositol phosphates. We found that the basal level of [3H]inositol trisphosphate, [3H]inositol bisphosphate and [3H]inositol monophosphate decreased following the stimulation of the D2 receptor. The rank order of potency was quinpirole (IC50 5 nM) greater than lisuride (IC50 8 nM) greater than RU 24213 (IC50 50 nM) greater than dopamine (IC50 200 nM). In contrast, selective D1 receptor stimulation by fenoldopam did not alter the inositol monophosphate, inositol bisphosphate and inositol trisphosphate content. The quinpirole effect was prevented by selective D2 antagonists, such as domperidone and L-sulpiride (both 5 microM) while it was unaffected by the selective D1 antagonist SCH 23390 (100 nM) and by the pharmacologically inactive D-isomer of sulpiride. Our data indicate that the activation of striatal D2 receptors leads to the inhibition of inositol phosphate production.

Animals↗
PubMed1992

Characterization of receptors for substance P in human astrocytoma cells: radioligand binding and inositol phosphate formation.

UC11 cells, derived from a human astrocytoma, have a high density of functional substance P receptors. Radioligand binding studies were conducted with the highly selective neurokinin-1 receptor ligand [3H][Sar9,Met(O2)11]-substance P. Kinetic binding experiments conducted at 4 degrees C yielded an association rate constant k1 of 1.86 x 10(7) M-1 min-1, a dissociation rate constant k-1 of 0.00478 min-1, and a calculated kinetic KD of 257 pM. Saturation binding experiments yielded average values of KD = 447 +/- 103 pM, Bmax = 862 +/- 93 fmol/mg of protein. This Bmax corresponds to more than 150,000 binding sites/cell. Competition binding experiments with unlabeled [Sar9,Met(O2)11]-substance P yielded average values of KD = 491 +/- 48 pM and Bmax = 912 +/- 67 fmol/mg of protein. In [3H]inositol-labeled cells, substance P induced a robust inositol phosphate formation. Inositol trisphosphate levels increased as much as 20-fold within approximately 15 s of addition of substance P. This inositol trisphosphate formation was transient and had returned to baseline within the first 60-120 s. Inositol monophosphate formation, however, was linear for at least 2 h. Structure activity data on binding and inositol monophosphate formation confirmed the presence of a neurokinin-1 receptor subtype in these cells. Thus, the UC11 cell should be a useful model cell for delineating the physiological role of substance P receptors in astrocytes.

Astrocytoma↗
PubMed1987

Zymosan-induced release of inositol phosphates at resting cytosolic Ca2+ concentrations in macrophages.

Hydrolysis of polyphosphoinositides by phosphodiesterase has been demonstrated to be involved in the control of cytosolic Ca2+ concentrations. The stimulation of Ca2+ ionophores of the release of inositol phosphates in macrophages, and other cells, together with the Ca2+ requirements for zymosan-induced phospholipase C activation, make unclear the relationship between Ca2+ mobilization and polyphosphoinositide hydrolysis. The results in the present paper strongly suggest that, for zymosan-induced phospholipase C activation, a previous increase in cytosolic Ca2+ is not a required event. These results also show that zymosan-activated release of inositol phosphates may be mediated by a guanine-nucleotide-binding protein.

Animals↗
PubMed1993

Effects of pertussis and cholera toxin on the interferon-gamma stimulated immunocytochemical staining of ICAM-1 and inositol phosphate formation in a human renal carcinoma cell line.

We have recently shown that interferon-gamma (IFN-gamma) stimulated immunocytochemical staining of the intercellular adhesion molecule ICAM-1 may be dependent on inositol phosphate formation in the human renal carcinoma cell line CaKi-1. In the present study we investigated the possible role of GTP-binding proteins (G-proteins) during IFN-gamma signalling. Preincubation of CaKi-1 cells for 24 h with increasing amounts of pertussis toxin (PT) or cholera toxin (CT), two regulators of G-protein activity, inhibited IFN-gamma induced ICAM-1 staining. Preincubation with PT or CT for 24 h also inhibited IFN-gamma induced inositol 1-monophosphate (Ins 1-P), inositol 1,4 bisphosphate (Ins 1,4-P2) and inositol 1,4,5 trisphosphate (Ins 1,4,5-P3) formation. Our findings suggest that IFN-gamma induced ICAM-1 staining and inositol phosphate formation in CaKi-1 cells is dependent on a PT and CT sensitive signalling pathway. This may reflect a role for G-proteins in the coupling of IFN-gamma receptor activation and phospholipase C catalyzed phosphoinositide hydrolysis.

Carcinoma, Renal Cell↗
PubMed1988

Modulation of the accumulation of inositol phosphates and the mobilization of calcium in aortic myocytes.

In vascular smooth muscle cells the phorbol ester, 12-O-tetradecanoyl phorbol 13-acetate (TPA), a potent activator of C-kinase, inhibited the accumulation of inositol phosphates and the mobilization of calcium produced by several agonists. In the same way, TPA inhibited the fluoride-induced activation of phosphoinositide metabolism. These results suggest a C-kinase action at a post-receptor level. Moreover, the fluoride-induced accumulation of inositol phosphates shows the presence of one or more guanine nucleotide-binding proteins (G-proteins) in the regulation of receptor-phospholipase C coupling. This was confirmed by the use of N-ethylmaleimide and pertussis toxin. These results support the view that, in addition to the induction of sustained contractions, C-kinase can activate negative feedback mechanisms in aortic myocytes.

Animals↗
PubMed1996

Mastoparan elicits prostaglandin E2 generation and inhibits inositol phosphate accumulation via different mechanisms in rabbit astrocytes.

The effects of mastoparan on phosphoinositide hydrolysis and prostaglandin E2 (PGE2) generation were investigated in astrocytes cultured from rabbit brain. Mastoparan inhibited the accumulations of [3H]inositol phosphates induced by bradykinin (1 microM) in a time- and concentration-dependent manner. Mastoparan (3-30 microM) also released PGE2 in a time- and concentration-dependent manner. Mastoparan-induced release of PGE2 was inhibited by indomethacin, a cyclooxygenase inhibitor, by dexamethasone, a steroidal anti-inflammatory drug, and by pertussis toxin, an inactivator of some G proteins, such as Gi and Go. Mastoparan also caused [3H]arachidonic acid liberation, which was inhibited by dexamethasone or pertussis toxin. In contrast, indomethacin, dexamethasone and pertussis toxin failed to attenuate mastoparan-induced inhibition of [3H]inositol phosphate accumulation induced by bradykinin. Thus, mastoparan-induced inhibition of phosphoinositide hydrolysis does not involve pertussis toxin-sensitive G protein nor arachidonic acid metabolites. In addition to the inhibition of phospholipase C, mastoparan activates phospholipase A2 through pertussis toxin-sensitive G protein.

Animals↗
PubMed1992

Effect of prenatal exposure to tianeptine on different neurotransmitter receptors and 5-HT-stimulated inositol phosphate formation in rat brain.

Tianeptine, an antidepressant drug enhancing 5-HT uptake, was given to pregnant rats in the last 15 days of gestation and different neurotransmitter receptors as well as 5-HT2 receptor-linked inositol phosphate formation were measured in the brains of the offspring. Prenatal exposure to tianeptine significantly decreased the density of 3H-imipramine binding sites in the cerebral cortex of the pups without affecting beta-adrenoceptors, serotonin 5-HT2 and 5-HT1B receptors or inositol phosphate formation after a 5-HT challenge. Striatal dopamine D2 receptors labelled with 3H-spiroperidol were not changed but an apparent increase in the affinity of dopamine was noticed in the pups prenatally exposed to the drug. The results show that the neurochemical profile of tianeptine markedly differs from that of most antidepressants.

Animals↗