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PubMed1989

Interactions of formylmethionyl-leucyl-phenylalanine, adenosine, and phosphodiesterase inhibitors in human monocytes. Effects on superoxide release, inositol phosphates and cAMP.

Cessation of the fMLF-induced burst of human monocyte superoxide release was associated with a rise in cAMP. This was not due to inhibition of phosphodiesterase (PDE), the major form of which was the PDE IV isozyme. The action of burst inhibitors did not correlate with cAMP levels: Rolipram, a PDe IV inhibitor, increased cAMP 6-fold, with minimal effects on the burst; whereas theophylline increased cAMP less than 2-fold but decreased the burst to less than half. Although theophylline and the adenylate cyclase activator, adenosine, inhibited fMLF-induced superoxide release, they did not inhibit production of inositol phosphates. Thus, these studies on inhibition of superoxide release implicated neither cAMP nor inositol phosphates.

Adenosine↗

PubMed1988

Fluoride stimulates the accumulation of inositol phosphates, increases intracellular free calcium, and inhibits parathyroid hormone release in dispersed bovine parathyroid cells.

The stimulation of polyphosphoinositide (PPI) turnover is associated with cellular activation and hormone secretion in numerous systems. GTP-binding proteins appear to couple receptors to phospholipase-C-mediated PPI breakdown. We assessed the effects of fluoride, an activator of GTP-binding proteins, on inositol phosphate accumulation, intracellular free Ca2+ [(Ca2+)i], cAMP content, and PTH release in dispersed bovine parathyroid cells. Sodium fluoride (5-30 mM) produced marked dose-dependent increases in inositol phosphates. With anion exchange HPLC, we confirmed that 30 mM fluoride stimulated a rapid increase in 1,4,5-inositol trisphosphate, a potent Ca2+-mobilizing compound. Using the Ca2+-sensitive probe fura-2, we determined that 30 mM fluoride increased [Ca2+]i from 339 +/- 9 to 650 +/- 39 nM (n = 8) within 30-60 sec at 1 mM extracellular Ca2+. After the depletion of extracellular Ca2+ by the addition of 1 mM EGTA, 30 mM fluoride increased [Ca2+]i 45 +/- 9% (n = 4), indicating that fluoride can mobilize intracellular Ca2+ stores. Fluoride (1-30 mM) also inhibited PTH release in dose-dependent fashion. Fluoride (30 mM) produced 72.8 +/- 4.2% suppression of maximal low Ca2+-stimulated PTH release comparable to the 83.7 +/- 3.7% inhibition by 2.0 mM extracellular Ca2+. Since changes in both [Ca2+]i and cAMP regulate PTH release, we measured the effect of fluoride on intracellular cAMP. Fluoride did not detectably change basal cAMP content, but it reduced forskolin-stimulated increases in cAMP. We conclude that fluoride may activate at least two GTP-dependent processes in parathyroid cells, resulting in PPI breakdown and cAMP accumulation. While both may contribute to the fluoride-induced suppression of PTH release, our findings suggest that the stimulation of PPI turnover leads to inhibition of PTH secretion.

Animals↗

PubMed1991

The effect of ischaemia and reperfusion on sarcolemmal inositol phospholipid and cytosolic inositol phosphate metabolism in the isolated perfused rat heart.

In this study the mass of polyphosphoinositides as well as the turnover of [3H]inositol phospholipids and [3H]inositol phosphates during ischaemia and short periods of reperfusion were studied in the isolated perfused rat heart. Since the phosphoinositides located within the sarcolemma are precursors for release of inositoltrisphosphate (InsP3) and diacylglycerol, sarcolemmal membranes (rather than whole tissue) isolated at the end of the experimental procedure, were used. Hearts were prelabelled with [3H]inositol and subsequently perfused with 10 mM LiCl to block the phosphatidylinositol (PI) pathway. The results showed that 20 min of global ischaemia depressed the amount of [3H]inositol present in both sarcolemmal phosphatidylinositol-4-phosphate (PI-4-P) and phsophatidylinositol-4,5-bisphosphate (PI-4,5-P2), as well as in the cytosolic [3H]inositol phosphates, [3H]InsP2 and [3H]InsP3. The mass of the sarcolemmal inositol phospholipids remained unchanged during ischaemia. Reperfusion caused an immediate (within 30 sec) increase in the amount of [3H]inositol in sarcolemmal PI, PI-4-P and PI-4,5-P2. PI-4-P levels showed a transient increase after 30 seconds postischaemic reperfusion, while the mass of the other sarcolemmal inositol phospholipids, PI and PI-4,5-P2, remained unchanged. [3H]InsP, [3H]InsP2 and [3H]InsP3 also increased significantly in comparison to ischaemic hearts after only 30 sec postischaemic reperfusion. In summary, the results obtained indicate inhibition of the PI pathway during ischaemia with an immediate significant stimulation upon reperfusion. In view of the capacity of InsP3 to mobilize Ca2+, the possibility exists that stimulation of this pathway during reperfusion may play a role in the intracellular Ca2+ overload, characteristic of postischaemic reperfusion.

Animals↗

PubMed1986

Cyclic GMP formation and inositol phosphate accumulation do not share common origins in rat brain slices.

Cyclic GMP formation and inositol phospholipid hydrolysis were studied in rat brain slices to determine if the two processes have common origins. Muscarinic cholinergic stimulation enhanced [3H]inositol phosphate ([ 3H]IP) accumulation from slices prelabelled with [3H]inositol but did not affect cyclic GMP formation in the cortex, striatum, or cerebellum. An elevated level of extracellular K+ stimulated accumulation of both cyclic GMP and [3H]IP in cortex slices. The former, but not the latter, was reduced by lipoxygenase and phospholipase A2 inhibition. Calcium channel activation enhanced and blockade reduced K+-stimulated [3H]IP formation without affecting the cyclic GMP level, and there were differences in the Ca2+ requirements for the two responses. Thus, there is no support for the concept that guanylate cyclase activation inevitably accompanies inositol phospholipid breakdown, and the evidence presented demonstrates that K+ stimulation promotes cyclic GMP and [3H]IP accumulation by different transducing pathways.

1-Methyl-3-isobutylxanthine↗

PubMed1987

A rapid separation method for inositol phosphates and their isomers.

A technique is described using ACCELL QMA anion-exchange SEP-PAKs (Waters Associates) with ammonium formate-based solutions, whereby a sample can be processed within minutes to yield resolution of inositol phosphates. Isomers of inositol trisphosphate can then be separated by using this technique in combination with a rapid (5-6 min) isocratic h.p.l.c. procedure. The use of QMA SEP-PAKs offers a degree of reproducibility comparable with that of h.p.l.c. while maintaining the capacity for automation, allowing large numbers of samples to be processed rapidly.

Chromatography, High Pressure Liquid↗

PubMed1989

Platelet-activating factor increases inositol phosphate production and cytosolic free Ca2+ concentrations in cultured rat Kupffer cells.

Platelet-activating factor (PAF) stimulates glycogenolysis in perfused livers but not in isolated hepatocytes [(1984) J. Biol. Chem. 259, 8685-8688]. PAF-induced glycogenolysis in liver is associated closely with a pronounced constriction of the hepatic vasculature [(1986) J. Biol. Chem. 261, 644-649]. These and other observations suggest that PAF stimulates glycogenolysis in liver indirectly by interactions with cells other than hepatocytes. We have evaluated effects of PAF on hepatic Kupffer cells, which regulate flow through the hepatic sinusoids. Application of PAF to [3H]inositol-labeled Kupffer cells produced dose-dependent increases in [3H]inositol phosphates with an EC50 value of 4 x 10(-10) M. Increases in inositol phosphate production in response to PAF were inhibited by a specific PAF receptor antagonist, SRI 63-675 (2 x 10(-7) M), and stimulus of protein kinase C, phorbol 12-myristate 13-acetate (1 x 10(-7) M). Measurements of cytosolic free Ca2+ concentrations ([Ca2+]i) in single Kupffer cells loaded with Fura-2 demonstrated that application of PAF (2 x 10(-9) M) resulted in significant increases in [Ca2+]i. These observations lead us to propose that interactions of PAF with Kupffer cells may result in the hemodynamic and metabolic responses to PAF in liver.

Animals↗

PubMed1989

Microfilaments and cellular signal transduction: effect of cytochalasin D on the production of cAMP, inositol phosphates, and on calcium movements in rat parotid glands.

In rat parotid glands, the involvement of the microfilament system in the cellular signal transmission mechanism was tested by measuring the effect of cytochalasin D (which disturbs the microfilament system) on the production of intracellular second messengers. Cytochalasin D (CD) did not affect unstimulated calcium movements (measured by the 45Ca efflux technique) or inositol phosphate production or cAMP accumulation. Neither did it modify the generation of intracellular second messengers induced by activation of the cholinergic muscarinic receptor (calcium and inositol phosphates). CD dit not affect the cAMP accumulation induced by the activation of the beta-adrenergic receptor whereas it strongly inhibited the calcium movements induced by activation of the same receptor. These data suggest that, in rat parotid glands, calcium movements, induced by beta-adrenergic receptor stimulation need an intact microfilament system to occur, whereas the muscarinic pathway (via IP3) does not.

Animals↗

PubMed1989

Cyclic and noncyclic inositol phosphates are formed at different ratios by phospholipase C isozymes.

The cyclic inositol phosphate content in the product of PLC-beta, gamma, and delta mediated cleavage of three phosphoinositides, PtdIns, PtdIns(4)p, and PtdIns(4,5)P2, was measured under several different experimental conditions. The ratio of cyclic to noncyclic product generally decreased in the order PLC-beta greater than PLC-delta greater than PLC-gamma. For all three enzymes the ratio decreased in the order PtdIns greater than PtdIns(4)P greater than PtdIns(4,5)P2. For all combinations of the three enzymes and three substrates cyclic product content was always higher at pH 5.5 than at pH 7.0. The effect of Ca2+ on the ratio of cyclic to noncyclic was also measured. The ratio remained constant between 0.5 microM and 2 mM for PtdIns. For PtdIns(4)P and PtdIns(4,5)P2, the ratios were unchanged between 0.5 and 500 microM, but increased abruptly at millimolar Ca2+ concentrations.

Animals↗

PubMed1991

Noradrenaline and endothelin-stimulated inositol phosphate formation in arterial smooth muscle from rabbits with perinephritis hypertension.

Total inositol phosphate (IP) formation was measured in the aorta and femoral artery from rabbits at 1, 2, and 6 weeks after kidney wrapping, at which times the mean arterial pressures were 88 +/- 4, 96 +/- 3 and 126 +/- 7 (control = 74 +/- 3) mmHg. Noradrenaline (10(-7)-10(-4) M)-stimulated IP formation was increased in the aorta and femoral artery from hypertensive rabbits at 2 weeks (e.g., aorta noradrenaline 10(-6) M sham = 105 +/- 14%, hypertensive = 164 +/- 20% of control). In contrast, endothelin-1-stimulated IP formation was unchanged at 2 weeks. Noradrenaline-stimulated IP formation was unchanged at 1 and 6 weeks. Basal IP formation was not significantly different in normotensive and hypertensive animals. In perinephritis hypertension, there is an alteration in phosphatidylinositol metabolism in arterial smooth muscle at the time when blood pressure is rising rapidly. This alteration may affect a specific phosphatidylinositol pool that is linked to the alpha-adrenoceptor but not to the endothelin-1 receptor.

Animals↗

PubMed1991

Synergistic interactions between alpha 1- and alpha 2-adrenergic receptors in activating 3H-inositol phosphate formation in primary glial cell cultures.

Norepinephrine (NE)-stimulated 3H-inositol phosphate (3H-InsP) formation in primary glial cell cultures is thought to be due to alpha 1-adrenergic receptor activation. Surprisingly, the alpha 1-selective agonists phenylephrine and methoxamine showed only 12-21% of the intrinsic activity of NE in activating this response. Although the alpha 2-selective agonist UK 14,304 was itself inactive, inclusion of UK 14,304 increased the response to the alpha 1-selective agonists by about threefold. This increase was concentration-dependent and occurred at all time points examined. 6-Fluoro-NE and alpha-methyl-NE mimicked the effect of NE in glial cultures, although with lower potencies. However, several partial agonists were ineffective in activating this response, in both the presence and absence of UK 14,304. Synergistic interactions were not observed for alpha 1-mediated responses in slices of rat cerebral cortex, either for formation of 3H-InsPs or potentiation of isoproterenol- or adenosine-stimulated cyclic AMP accumulation. Both UK 14,304 and phenylephrine inhibited NE-stimulated 3H-InsP formation in concentrations similar to those necessary to activate this response directly. These results suggest that NE activates 3H-InsP formation in primary glial cultures by synergistic actions on both alpha 1- and alpha 2-adrenergic receptors. The agonists UK 14,304 and phenylephrine also can act to inhibit the response to NE competitively.

Adrenergic alpha-Agonists↗

PubMed1990

Pertussis toxin inhibition of anti-immunoglobulin-stimulated proliferation and inositol phosphate formation.

A variety of receptor agonists activate cells by stimulating polyphosphoinositide hydrolysis. Increasing evidence supports the concept that receptor-stimulated phosphoinositide hydrolysis is mediated by a guanosine triphosphate binding protein, which in some cell systems is inhibited by pertussis toxin through ADP-ribosylation. The cross-linking of membrane immunoglobulin by antigen or anti-Ig stimulates phosphoinositide hydrolysis resulting in the formation of inositol phosphate and diacylglycerol which act as second messengers in initiating B lymphocyte activation. In this report, we demonstrate that anti-Ig-stimulated inositol phosphate formation is enhanced by the nonhydrolyzable guanosine triphosphate analogue, GppNHp, in permeabilized B lymphocytes and also inhibited by pretreatment of intact cells with pertussis toxin. This latter effect is associated with the pertussis toxin-catalyzed ADP-ribosylation of a 41-kDa membrane protein which is of the same molecular weight as the guanosine triphosphate binding protein reported to mediate receptor-stimulated phosphoinositide hydrolysis in other cellular receptor systems. B lymphocyte proliferation induced by agents such as lipopolysaccharide and PMA plus calcium ionophore, which activate cellular proliferation without stimulating phosphoinositide breakdown, is not inhibited by pertussis toxin. We conclude that anti-Ig activation of B lymphocytes contains pertussis toxin- and guanosine triphosphate-sensitive components which are involved in regulating phosphoinositide breakdown and initiating cellular activation.

Animals↗

PubMed1986

Differential effects of spermine on aggregation, inositol phosphate formation and protein phosphorylation in human platelets in response to thrombin, arachidonic acid and lysophosphatidic acid.

Platelet aggregation stimulated by thrombin, arachidonic acid or lysophosphatidic acid is associated with rapid phosphorylation of two platelet proteins, myosin light chain and a 47 kDa protein. The polyamine, spermine, inhibited platelet aggregation stimulated by all three agents. Spermine inhibited thrombin-stimulated phosphorylation of myosin light chain and the 47 kDa proteins as well as thrombin-induced production of the inositol phosphates and phosphatidic acid. In contrast, spermine did not inhibit phosphorylation of either protein or the formation of inositol phosphates and phosphatidic acid in response to arachidonic acid or lysophosphatidic acid. Although spermine has been demonstrated to inhibit both phosphatidylinositol-specific phospholipase C and calcium-dependent protein kinases in cell free systems, these results suggest that, in the intact platelet, spermine does not directly inhibit these enzymes. Inhibition of aggregation stimulated by arachidonic acid and lysophosphatidic acid is secondary to interference with platelet-platelet interaction but not with platelet activation. In contrast, spermine inhibits thrombin-induced platelet activation. This thrombin-specific inhibition may be related to interference with the binding of thrombin to its receptor or to its catalytic substrate on the cell surface.

Arachidonic Acid↗

PubMed1990

Secretory agonists stimulate a rise in intracellular cyclic AMP but not Ca2+ and inositol phosphates in cultured rat epididymal epithelium.

Primary monolayer cultures of rat epididymal cells have been shown to secrete chloride and bicarbonate when stimulated with beta-adrenergic agents, humoral agents and vasoactive peptides. The intracellular messengers mediating the secretory response are unknown. In this study intracellular AMP, Ca2+ and inositol phosphates were measured in epididymal monolayers at rest and upon stimulation with various secretory agonists. Adrenaline, forskolin, lysylbradykinin, prostaglandin, endothelin, angiotensin II, antidiuretic hormone and vasoactive intestinal peptide at concentrations that stimulate anion secretion caused a rise in intracellular cyclic AMP. The increase in cyclic AMP by adrenaline was blocked by propranolol but not by phentolamine. Studies of the concentration-effect relationships showed that for adrenaline and endothelin the EC50 for stimulation of cyclic AMP was higher than that for stimulation of anion secretion. None of these agonists affects intracellular Ca2+ concentration and inositol phosphate contents in epididymal monolayers. Ca2+ ionophores A21387, ionomycin and erythrosin B (with irradiation with white light), at concentrations that stimulate anion secretion, also stimulated a rise in intracellular cyclic AMP and concomitantly increased intracellular Ca2+. The increase in cyclic AMP was dependent on extracellular Ca2+. It is not known whether the secretory response to Ca2+ ionophores was mediated by an increase in cell Ca2+ per se, or cyclic AMP. However, it can be concluded that cyclic AMP is the second messenger which mediates the secretory responses to physiological stimuli.

Adrenergic Agonists↗

PubMed1986

Scorpion venom (Leiurus quinquestriatus) elicits accumulations of inositol phosphates and cyclic AMP in guinea pig cortical synaptoneurosomes.

Scorpion (Leiurus quinquestriatus) venom (ScV) stimulated accumulations of cyclic AMP and turnover of phosphatidylinositol in guinea pig cortical synaptoneurosomes. The concentrations of ScV that were necessary to increase cyclic [3H]AMP accumulation were lower than those required to stimulate formation of [3H]inositol phosphates from phosphatidylinositol. In the presence of 10 microM 2-chloroadenosine, ScV induced a dose-dependent synergistic accumulation of cyclic AMP with an EC50 value that was comparable to the EC50 required for stimulation of phosphatidylinositol turnover. Tetrodotoxin partially inhibited cyclic AMP accumulations elicited by ScV indicating that at least part of such responses are due to activation of voltage-dependent sodium channel. Tetrodotoxin virtually completely blocked formation of inositol phosphate stimulated by ScV. High concentrations of Mg2+ (30 mM) did not block responses to ScV indicating that release of neurotransmitters was not involved. Membrane potential changes could not be detected at concentrations of ScV that triggered the biochemical responses. Stimulation of phosphatidylinositol turnover by ScV appears to depend on an increase in influx of Na+ in synaptoneurosomes, presumably due to slowing of the inactivation of voltage-dependent sodium channels by alpha-scorpion toxin, a component of ScV. At least in part, the stimulation of cyclic AMP accumulation by ScV correlates with increases in phosphatidylinositol turnover.

2-Chloroadenosine↗

PubMed1991

Interaction between PAF and drugs that stimulate formation of inositol phosphates.

1. We examined the effect of platelet-activating factor (PAF) on alpha 1-adrenergic and muscarinic cholinergic receptors in the membranes of rat parotid and the functional responses to norepinephrine (NE) and carbamylcholine (CCh) in exocrine secretion. 2. Pretreatment of parotid slices with 1 microM PAF caused a significant decrease the density of [3H]prazosin and [3H]quinuclidinyl benzilate binding sites without a change in the affinity. 3. In functional studies, pretreatment of parotid slices with 1 microM PAF markedly reduced the increase in intracellular 3H-labeling of inositol phosphates induced by NE and CCh. However, the EC50 values for NE and CCh stimulation of [3H]inositol phosphates in 1 microM PAF treated slices were significantly higher when compared to those of controls. 4. In addition, NE- and CCh-induced K+ release from parotid slices were also inhibited by PAF (1 microM) treatment. CV3988, a PAF antagonist, protected against these PAF-induced changes. 5. These results suggests that PAF-induced downregulation of alpha 1-adrenergic and muscarinic cholinergic receptors is mediated through specific PAF receptors in rat parotid glands, and that PAF could be a mediator which alters alpha 1-adrenergic and muscarinic cholinergic responses.

Animals↗

PubMed2006

Inositol phosphate metabolomics: merging genetic perturbation with modernized radiolabeling methods.

Recent discoveries that provide a link between inositol phosphate (IP) signaling and fundamental cellular processes evoke many exciting new hypotheses about IP function, and underscore the importance of understanding how IP synthesis is regulated. Central to studies of IP metabolism is the essential development of efficient, fast, and reproducible methods for quantitative analysis of IPs in systems ranging from simple cell cultures to more complex tissues and whole organisms. Additionally, in many cases there is a need to pharmacologically and/or genetically alter IP kinase and phosphatase activities in order to visualize low abundance inositol signaling messengers. Here, we describe updated methods for rapid analysis of IP metabolism in normal and genetically manipulated Saccharomyces cerevisiae, Arabidopsis thaliana, Drosophila melanogaster, Mus musculus, and Homo sapiens.

Animals↗

PubMed1989

Regulation of surface IgM- and IgD-mediated inositol phosphate formation and Ca2+ mobilization in murine B lymphocytes.

Cross-linking of surface IgM or IgD receptors on B cells initiates a signaling cascade involving the activation of an (uncharacterized) G-protein: this in turn activates a polyphosphoinositide-specific phosphodiesterase (PPI-PDE), thereby leading to the release of inositol phosphates. In order to investigate if the two isotypes of sIg share a common G-protein, we stimulated B cells sequentially with anti-mu and anti-delta antibodies. Ligation of either class of receptor for 1 h led to the activation of the PPI-PDE, which persisted for several hours. However, this was accompanied by inhibition of further stimulation of the enzyme via the heterologous receptors. This desensitization was shown to operate at the level of the coupling between G-protein and the PPI-PDE. These effects waned after 4-8 h of stimulation, when signaling via the heterologous receptors had essentially returned to normal. In addition, stimulation of B cells by anti-mu and anti-delta together did not elicit additive responses, either in terms of increases in inositol phosphate production, or in terms of increases in intracellular Ca2+ levels. Taken together, these results indicate that sIgM and IgD receptors share a common G-protein and that signaling via these receptors is under both positive and negative feedback control. The mechanisms involved are unknown, but these effects may well be due to modulation of the activities of components of the signaling cascade by protein kinase C.

Animals↗

PubMed1994

Second messenger specificity of the inositol trisphosphate receptor: reappraisal based on novel inositol phosphates.

To further understand how the second messenger D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] interacts with its intracellular receptor, we injected 47 highly purified inositol phosphate (InsP) positional isomers in Xenopus oocytes and compared their potency in releasing intracellular Ca2+. The potency of the Ca(2+)-releasing InsPs spanned four orders of magnitude. Seven compounds, including the novel inositol 1,2,4,5-tetrakisphosphate [D/L-Ins (1,2,4,5)P4] and D/L-Ins(1,4,6)P3, had a very high potency. All of these highly active InsPs shared the following structure: two D-trans-equatorial phosphates (eq-P) and one equatorial hydroxyl (eq-OH) attached to ring carbons D-4, D-5, and D-6 (or to the structurally equivalent D-1, D-6, and D-5 carbons). This permissive structure was not sufficient for Ca2+ release, because it was also found in two inactive compounds, Ins(1,6)P2 and Ins(1,3,6)P3. To be active, InsPs also required the structural equivalent of a D-3 eq-OH and/or a D-1 eq-P. Together, our data reveal how the structure of the InsP molecule affects its ability to release Ca2+.

Animals↗