Metabolism of myo-inositol phosphates and the alternative pathway in generation of myo-inositol trisphosphate involved in calcium mobilization in plants.
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Abscisic Acid↗
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Thyroid hormones regulate the formation of inositol phosphate in response to thyrotropin-releasing hormone in rat anterior pituitaries.
The effects of thyroid hormones on TSH secretion and inositol phospholipid hydrolysis in response to thyrotropin-releasing hormone (TRH) in rat anterior pituitaries were examined. Experimental hypothyroidism caused a significant increase in [3H]inositol phosphate ([3H]IP) formation in response to TRH in rat anterior pituitaries with a concomitant elevation of blood TSH. In contrast, administration of thyroxine (T4) to hypothyroid rats resulted in a complete restoration of blood TSH and TRH-stimulated [3H]IP formation to the euthyroid control value. Furthermore, in vitro pre-treatment of anterior pituitaries with triiodothyronine (T3) produced a dose-dependent decrease in both TSH secretion and the formation of [3H]IP in response to TRH. These results indicate that thyroid hormones regulate TRH receptor-linked inositol phospholipid hydrolysis in the rat anterior pituitary, suggesting that negative feedback action of thyroid hormone occurs at post receptor event in the rat anterior pituitary, which may, to a certain extent, be responsible for the underlying mechanism of T3 inhibition of TSH secretion.
Animals↗
Protein kinase C down-regulation in astrocytes: differential effects on agonist-stimulated inositol phosphate accumulation.
Prolonged phorbol ester treatment abolished protein kinase C (PKC) activity for over 48 h in cortical astrocyte cultures. Receptor-stimulated inositol phospholipid breakdown in these cultures subsequent to PKC depletion produced either enhanced, depressed or unchanged responses depending upon the agonist used. Noradrenaline-, ATP-, histamine- and glutamate-evoked [3H]-inositol phosphate accumulations were potentiated to varying degrees in PKC-depleted cultures whilst those evoked by carbachol and NaF were reduced and unchanged respectively. Analysis of the individual metabolites of inositol phospholipid metabolism formed in response to noradrenaline in PKC-depleted astrocytes revealed potentiated accumulations of radiolabelled glycerophosphoinositol (GPI), inositol monophosphate (IP1) and inositol bisphosphate (IP2) but not inositol trisphosphate (IP3) when compared to controls. Under the same conditions, accumulations of radiolabelled IP1 and IP2 were reduced and those of GPI and IP3 unchanged in carbachol-treated cultures. These results suggest that astrocyte receptors coupled to inositol phospholipid metabolism are differentially regulated by PKC.
Adenosine Triphosphate↗
Complexation studies on inositol-phosphates. II. Alkali-metal complexes of D-myo-inositol 1,2,6 trisphosphate.
The complexation properties of the D-myo-inositol 1,2,6 trisphosphate (Ins(1,2,6)P3) towards Li+, Na+, K+, Rb+, and Cs+ cations were studied at 25 degrees C in a 0.1 M tetra-n-butylammonium bromide medium. For all cations, mononuclear and protonated species were found. For smaller cations (Li+, Na+, and K+) a dinuclear complex was also put into evidence. The main characteristic of the complexes is its high stability; and of the ligand, its nonselectivity. The Ins(1,2,6)P3-K system was ascertained using Sammartano's method which additionally enabled the influence of various K+ concentrations on the protonations constants to be considered.
Cations, Monovalent↗
Does the inositol phosphate signalling system function in the heart? A comparison of inositol lipid turnover in cardiac and smooth muscle.
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Animals↗
Autocrine biological effects of glycosyl inositol phosphate produced by reconstituted pig thyroid follicles: role of pertussis toxin sensitive G proteins.
We examine the autocrine activity of glycosyl inositol phosphate (InP-gly) on thyroid metabolism. The cAMP accumulation promoted by thyrotropin (TSH) or forskolin was modulated by InP-gly, stimulated by the lowest tested concentration (10(-8) M) and progressively inhibited by higher concentrations. Iodide uptake and iodine organification were decreased in a concentration-dependent manner by InP-gly alone, or in the presence of TSH. The IAP component of pertussis toxin blocked the inhibitory action of InP-gly on cAMP accumulation by reconstituted thyroid follicles (RTF), suggesting the participation of Gi protein. But the same treatment with IAP was without effect on iodine metabolism, suggesting that there is a second target for InP-gly, more distal than Gi protein, or coupled to another G protein which is insensitive to the toxin.
Animals↗
Stimulation of generation of inositol phosphates by carbamoylcholine and its inhibition by phorbol esters and iodide in dog thyroid cells.
The action of carbamoylcholine (Cchol), NaF and other agonists on the generation of inositol phosphates (IPs) was studied in dog thyroid slices prelabelled with myo-[2-3H]inositol. The stimulation by Cchol (0.1 microM-0.1 mM) of IPs accumulation through activation of a muscarinic receptor [Graff, Mockel, Laurent, Erneux & Dumont (1987) FEBS Lett. 210, 204-210] was pertussis- and cholera-toxin insensitive. Ins(1,4,5)P3, Ins(1,3,4)P3 and InsP4 were generated. NaF (5-20 mM) also increased IPs generation (Graff et al., 1987); this effect was potentiated by AlCl3 (10 microM) and unaffected by pertussis toxin. Although phorbol dibutyrate (5 microM) abolished the cholinergic stimulation of IPs generation (Graff et al., 1987), it did not affect the fluoride-induced response. Cchol and NaF did not require extracellular Ca2+ to exert their effect, and neither KCl-induced membrane depolarization nor ionophore A23187 (10 microM) had any influence on basal IPs levels, or on cholinergic stimulation. However, more stringent Ca2+ depletion with EGTA (0.1 or 1 mM) decreased basal IPs levels as well as the amplitude of the stimulation by Cchol without abolishing it. Dibutyryl cyclic AMP, forskolin, cholera toxin and prostaglandin E1 had no effect on basal IPs levels and did not decrease the response to Cchol. Iodide (4 or 40 microM) also strongly decreased the cholinergic action on IPs, this inhibition being relieved by methimazole (1 mM). Our data suggest that Cchol activates a phospholipase C hydrolysing PtdIns(4,5)P2 in the dog thyroid cell in a cyclic AMP-independent manner. This activation requires no extracellular Ca2+ and depends on a GTP-binding protein insensitive to both cholera toxin and requires no extracellular Ca2+ and depends on a GTP-binding protein insensitive to both cholera toxin and pertussis toxin. The data are consistent with a rapid metabolism of Ins(1,4,5)P3 to Ins(1,3,4)P3 via the Ins(1,4,5)P3 3-kinase pathway, followed by dephosphorylation by a 5-phosphomonoesterase. Indeed, a Ca2+-sensitive InsP3 3-kinase activity was demonstrated in tissue homogenate. Stimulation of protein kinase C and an organified form of iodine inhibit the Cchol-induced IPs generation. The negative feedback of activated protein kinase C could be exerted at the level of the receptor or of the receptor-G-protein interaction.
Aluminum↗
Regulation of inositol phosphate metabolism in chemoattractant-stimulated human polymorphonuclear leukocytes. Definition of distinct dephosphorylation pathways for IP3 isomers.
The metabolism of the calcium mobilizing inositol-1,4,5-trisphosphate (IP3) isomer was studied in myo-[3H]inositol labeled, chemoattractant-stimulated human polymorphonuclear neutrophils (PMNs), and in PMN lysates. It was determined that 1,4,5-IP3 is metabolized in vitro by two distinct pathways: 1) by sequential dephosphorylation to 1,4-IP2, 4-IP1, and inositol or 2) by ATP dependent conversion to 1,3,4,5-IP4, followed by dephosphorylation to form 1,3,4-IP3, 3,4-IP2, 3-IP1, and inositol. In PMNs stimulated with 0.1 microM N-formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe), 1,4-IP2, 1,4,5-IP3, and IP4, were elevated by 5 s; whereas production of 1,3,4-IP3, 3,4-IP2, and IP1 occurred only after an initial lag (approximately 15 s). The predominant IP1 isomer formed in fMet-Leu-Phe-stimulated cells was 4-IP1. Production of 1,3,4-IP3 and 3,4-IP2 was markedly reduced (17 and 35% of control, respectively) in fMet-Leu-Phe-stimulated cells pretreated to prevent a rise in intracellular calcium ([Ca2+]i). PMNs were also stimulated with leukotriene B4 (LTB4) since this agent is a poor activator of the respiratory burst compared to fMet-Leu-Phe. Peak levels (5 s) of 1,4,5-IP3 were equivalent after stimulation with 0.1 microM fMet-Leu-Phe versus 0.1 microM LTB4 (320 +/- 38% versus 378 +/- 38% of control values, respectively; n = 5); however, at 30 s, 1,4,5-IP3 remained elevated only in fMet-Leu-Phe-stimulated cells. Similarly, elevation of [Ca2+]i was more prolonged in response to 0.1 microM fMet-Leu-Phe (greater than 3 min) versus LTB4 (1 min). Thus, signal transduction in PMNs may be modulated by both the duration of the initial 1,4,5-IP3 signal and by the metabolic pathway(s) utilized to convert this IP3 isomer to other, potentially active inositol phosphate products.
Adenosine Triphosphate↗
Inhibition of the carbachol-evoked synthesis of inositol phosphates by ototoxic drugs in the rat cochlea.
The ability of amikacin, neomycin, ethacrynate, mercuric chloride and cisplatin to alter the inositol phosphate (IP) signalling pathway was assessed in the 12-day-old rat cochlea, where the turnover of IPs is coupled to muscarinic receptors. This study was motivated by: (1) the demonstration of neomycin binding to phosphatidylinositol 4,5-biphosphate, the precursor of IPs, and (2) the fact that ototoxic drugs induce some common symptoms in outer hair cells. At concentrations below 1 mM, none of the compounds changed the control 3H-IP formation. Mercuric chloride, cisplatin and ethacrynate inhibited the carbachol-induced formation of IPs in a dose-dependent manner with IC50 values of 74,340 and 430 microM, respectively. The aminoglycosides were less efficient in reducing the carbachol-stimulated accumulation of IPs, since neither amikacin nor neomycin, both at 1 mM, had any significant effect. However, neomycin applied at 15 and 30 microM induced 29% and 43% of inhibition of the stimulated IP response. Finally, additive effects are obtained between some of the toxic drugs. The results suggest that a block of the IP transduction system, associated with the cholinergic efferent innervation of the organ of Corti, is a feature that may be involved in some types of ototoxicity. The inefficiency of aminoglycosides and the putative targets of the ototoxic agents are discussed.
Amikacin↗
Gonadotropin-releasing hormone (GnRH)-receptor coupling to inositol phosphate and prolactin production in GH3 cells stably transfected with rat GnRH receptor complementary deoxyribonucleic acid.
This study examines the relation between inositol phosphate (IP) production and PRL release in four GGH3 cell lines (GGH(3)1', GGH(3)2', GGH(3)6', and GGH(3)12'; lactotropic GH3 cells that have been stably transfected with rat GnRH receptor complementary DNA). Production of IPs is an early response of GGH3 cells to a GnRH agonist, measurable at 15-30 min and maximal at 60 min after treatment with Buserelin in [3H]inositol preloaded cells. In contrast, PRL release, which requires protein synthesis, is not measurable until 1-3 h and total cAMP production is not measurable until about 24 h (3). In one of the lines studied (GGH(3)2'), PRL was also released in response to TRH. Measurable expression of the PRL gene requires 1-2 days (2). All four lines produced IPs robustly after treatment with Buserelin, although the IP response to TRH is minimal in all lines, being the best in the GGH(3)2' line. Pretreatment of cells with cholera toxin (CTX) or pertussis toxin (PTX) attenuated TRH-induced IP production in GGH(3)1', GGH(3)2', or GGH(3)12' cells. No effect of CTX or PTX is measurable in GGH(3)6' cells in terms of TRH stimulation of IP production. In contrast, both toxins augment Buserelin-stimulated IP production in GGH(3)1' and GGH(3)6' cells, but have no action in the other two lines. Both CTX and PTX inhibit Buserelin-stimulated PRL production. This study suggests that IP production is the earliest measurable response of GGH3 cells to a GnRH agonist, although this event does not appear to be coupled to Buserelin-stimulated PRL release. Further, the studies with toxins suggest that Buserelin and TRH appear to regulate IP production by different mechanisms.
Animals↗
Uncoupling of ATP-induced inositol phosphate formation and Ca(2+) mobilization by phorbol ester in canine cultured tracheal epithelial cells.
The regulation of the increase in inositol phosphates (IPs) production and intracellular Ca(2+) concentration ([Ca(2+)](i)) by protein kinase C (PKC) was investigated in canine cultured tracheal epithelial cells (TECs). Pretreatment of TECs with phorbol 12-myristate 13-acetate (PMA, 1 microM) for 30 min attenuated the ATP- and UTP-induced IPs formation and Ca(2+) mobilization. The concentrations of PMA that gave half-maximal (EC(50)) inhibition of ATP- and UTP-induced IPs accumulation and an increase in [Ca(2+)](i) were 5-10 and 4-12 nM, respectively. Prior treatment of TECs with staurosporine (1 microM), a PKC inhibitor, partially inhibited the ability of PMA to attenuate ATP- and UTP-induced responses, suggesting that the inhibitory effect of PMA is mediated through the activation of PKC. Furthermore, analysis of cell extracts by Western blotting with antibodies against different PKC isozymes revealed that TECs expressed PKC-alpha, -betaI, -betaII, -gamma, -delta, -epsilon, -theta, and -zeta. With PMA treatment of the cells for various times, translocation of PKC-alpha, -betaI, -betaII, -gamma, -delta, -epsilon, and -theta from the cytosol to the membrane was seen after 5- and 30-min and 2- and 4-h treatment. However, 6-h treatment caused a partial down-regulation of these PKC isozymes. PKC-zeta was not significantly translocated and down-regulated at any of the times tested. In conclusion, these results suggest that activation of PKC may inhibit the phosphoinositide (PI) hydrolysis and consequently attenuate the [Ca(2+)](i) increase or inhibit independently both responses to ATP and UTP. The translocation of PKC-alpha, -betaI, -betaII, -delta, -epsilon, -gamma, and -theta induced by PMA caused an attenuation of ATP- and UTP-induced IPs accumulation and Ca(2+) mobilization in TECs.
Adenosine Triphosphate↗
Measurement of picomole amounts of any inositol phosphate isomer separable by h.p.l.c. by means of a bioluminescence assay.
An assay is described which allows the determination of the mass of any individual inositol phosphate (InsP) isomer by combining a popular h.p.l.c. separation method with simple desalting, dephosphorylation and final measurement of Ins liberated using an inositol dehydrogenase-NADH-linked bioluminescence reaction. The limit of sensitivity of this assay is about 1 pmol of Ins. routinely 5 pmol. About 40 mg wet wt. of guinea pig small intestine longitudinal smooth muscle contains 5 pmol of Ins(1,4,5)P3. For Inst(1,3,4)P3 or Ins(1,3,4,5)P4 slightly more smooth muscle is needed, and for major isomers of InsP1 or InsP2 10 mg wet wt. or less of tissue can be used. A 35 mm tissue culture plate with a confluent layer of rat fibroblasts contains about 30 pmol of Ins(1,4,5)P3. The method was applied to the measurement of the masses of Ins1P1. Ins4P1, Ins(1,4)P2, Ins(1,3,4)P3, Ins(1,4,5)P3, Ins(1,3,4,5)P4 and InsP5. The h.p.l.c. elution profiles of radiolabelled InsPS generated from [32P]Pi-labelled human Erythrocytes, [3H]Ins-labelled cultured rat fibroblasts and [3H]Ins-labelled smooth muscle fragments from guinea pig small intestine were compared with the h.p.l.c. elution profiles of their masses.
Animals↗
Epithio-11,12-methano-thromboxane A2 stimulates inositol phosphates accumulation in isolated canine mesenteric artery strips.
Epithio-11,12-methano-thromboxane A2 (STA2), a stable analog of thromboxane A2 (TXA2), stimulated inositol phosphates (IPs) accumulation in canine mesenteric artery strips, but not in cerebral (basilar) artery strips. When canine mesenteric artery strips were incubated with 0.1 microM [3H]myo-inositol for 15 min and then stimulated with 10 microM STA2 for 30 min, there was a significant increase in 3H-IPs accumulation as measured by anion exchange chromatography (2,028 +/- 204 and 3,526 +/- 210* dpm/mg protein for basal and stimulated accumulations, respectively; means +/- S.E.M., n = 3, *P less than 0.01, significantly different from the basal value). This effect of STA2 was dose-dependent with an EC50 value of 1.6 +/- 0.2 microM. The presence of equimolar concentrations of TXA2 receptor antagonists, either ONO-3708 (9,11-dimethylmethano-11,12-methano-13,14-dihydro-13-aza-14-oxo-15 -cyclopental- 16,17,18,19,20-pentanor-15-epi-thromboxane A2) or S-1452 (5Z-7-(3-endo-phenylsulfonylamino-(2.2.1)-bicyclohept- 2-exo-yl)heptenoic acid), completely blocked the effect of STA2. These results suggest the presence of TXA2 receptors coupled with IPs accumulation in canine mesenteric artery strips. The exact location of the TXA2 receptor-IPs system, however, remains unknown.
Animals↗
Biphasic formation of inositol phosphates in opsonized zymosan-stimulated human neutrophils.
Stimulation by serum-opsonized zymosan (SOZ) typically causes a biphasic rise in the cytosolic free Ca2+ concentration ([Ca2+]i) of human neutrophils. It consists of an initial slow Ca2+ release from internal pools lasting for 60 s, followed by a rapid but sustained influx of Ca2+. It was the aim of this study to elucidate the underlying mechanism of this atypical Ca2+ response. For this reason we analysed the production of inositol phosphates (InsPs) in myo-[3H]inositol labelled cells. Stimulation by SOZ within 10 s transiently elevated inositol trisphosphate (InsP3) by 1.50-fold. This response was followed by a second, more sustained 1.55-fold rise in InsP3 by 90 s. A similar, biphasic pattern of inositol tetrakisphosphate (InsP4) formation with 1.15- and 1.35-fold increases, respectively, was observed. The SOZ-induced formation of InsP3 was unaffected by the removal of extracellular Ca2+ by 1.4 mM EGTA. In contrast, the early accumulation of InsP4 was stronger and more prolonged and no second rise over the baseline level was seen in the absence of extracellular Ca2+. Under these conditions, the sudden exposure of Fura-2 AM loaded, SOZ-stimulated neutrophils to extracellular Ca2+ at a time point where InsP4 was the predominant InsP resulted in a marked increase in [Ca2+]i. Recalcification at a time point when InsP3 was the major InsP had no effect on [Ca2+]i. These findings suggest that in SOZ-stimulated neutrophils (1) the transient, first accumulation of InsP3 mediates the slow Ca2+ release from internal pools, and (2) the second, more pronounced formation of InsP4 triggers the Ca2+ influx.(ABSTRACT TRUNCATED AT 400 WORDS)
Blood↗
Inositol phosphates modulate human red blood cell Ca(2+)-adenosine triphosphatase activity in vitro by a guanine nucleotide regulatory protein.
D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] inhibits human red blood cell (RBC) Ca(2+)-stimulable, Mg(2+)-dependent adenosine triphosphatase (Ca(2+)-ATPase) activity in vitro. Because we have previously shown that adrenergic receptors exist on the human mature RBC membrane and can modulate Ca(2+)-ATPase activity, we examined the possibility that a guanine nucleotide regulatory protein (G protein) mediated the Ins(1,4,5)P3 effect. Guanosine 5'-O-(3-thiotrisphosphate) (GTP gamma S) 10(-4) mol/L also inhibited RBC Ca(2+)-ATPase activity. Pertussis toxin 200 ng/mL blocked the effects of both Ins(1,4,5)P3 and GTP gamma S on Ca(2+)-ATPase activity. In separate studies, pertussis toxin-catalyzed adenosine diphosphate (ADP) ribosylation was shown to occur in RBC membranes under conditions in which measurements of Ca(2+)-ATPase activity were performed. When Ins(1,4,5)P3 10(-7) mol/L and GTP gamma S 10(-6) mol/L were added to membranes concurrently, their inhibitory actions on the enzyme were additive. At greater concentrations of Ins(1,4,5)P3 (10(-6) to 10(-5) mol/L) and GTP gamma S (10(-4) mol/L), the inositol phosphate reversed the inhibitory effect of GTP gamma S. These observations indicate that the novel effect of Ins(1,4,5)P3 on the activity of a plasma membrane Ca(2+)-ATPase depends at least in part on the action of a pertussis toxin-susceptible G protein.
Adult↗
Use of Zn-pyrophosphatase in the high-performance liquid chromatographic analysis of cell extracts containing 32P-labelled inositol phosphates.
A simple method is described for eliminating the interference of pyrophosphate and pyrophosphorylated nucleosides in the high-performance liquid chromatographic determination of inositol 1,3,4-triphosphate and inositol 1,4,5-triphosphate of 32P-labelled extracts of cells. Treatment of the extract with pyrophosphatase, but substituting Zn2+ for Mg2+ as the cofactor, converts all nucleoside triphosphates and pyrophosphate to their di- and monoesters. Such change shifts their position in the elution profile, allowing a clear identification and quantification of the inositol phosphates. Typical overall recoveries near 80% or higher of added markers.
Chromatography, High Pressure Liquid↗
Hypothyroidism inhibits the formation of inositol phosphate in response to carbachol in the striatum of adult rat.
The effects of hypothyroidism on the muscarinic cholinergic receptor-coupled inositol phospholipid hydrolysis in the adult rat brain were examined. Tissue slices of striatum, hippocampus, and cortex from either euthyroid or hypothyroid rats were labeled with [3H]myoinositol and incubated with carbachol, a muscarinic cholinergic agonist. In other experiments, crude plasma membranes of each brain region obtained from either euthyroid or hypothyroid rats were incubated with [3H]N-methylquinuclidinyl benzilate ([3H]NMeQNB), a muscarinic cholinergic antagonist, in the presence or absence of atropine. Carbachol produced a significant increase in [3H]inositol phosphate ([3H]IP) formation in each brain region in a dose dependent manner. Hypothyroidism caused a marked decrease in carbachol-stimulated [3H]IP formation in the striatum, whereas it did not affect the formation of [3H]IP in the cortex or hippocampus. In contrast, the affinity constant and the maximal binding of [3H]NMeQNB to plasma membranes in these regions were not changed by hypothyroidism. The present results suggest that thyroid hormones might participate in regulating the muscarinic cholinergic neurotransmission in the striatum of adult rat.
Animals↗
Muscarinic stimulation of inositol phosphate accumulation and acid secretion in gastric fundic mucosal cells.
The muscarinic agonist, carbachol (CCh), was shown to stimulate the production of inositol phosphates (IP) in isolated cells from rabbit fundic mucosa. This stimulatory effect was time- and dose-dependent: EC50 values for IP1, IP2 and IP3 accumulation were not statistically different. The mean value was 30 +/- 8 microM (n = 6). The corresponding maximal stimulation (% of basal value) observed after 20 min incubation in the presence of 100 microM CCh was 160 +/- 15%. CCh-induced IP accumulation was abolished by atropine (Ki = 0.32 +/- 0.18 nM (n = 3)). The CCh concentrations leading to half-maximal inhibition of N-[3H]methylscopolamine binding and half-maximal IP accumulation were similar. The half-maximal value for CCh-induced aminopyrine accumulation was 8-times lower. These results indicate that IP3-mediated mobilization of intracellular Ca2+ might be involved in CCh-induced acid secretion by parietal cells.
Animals↗