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PubMed1997

Characterization of the pleckstrin homology domain of Btk as an inositol polyphosphate and phosphoinositide binding domain.

We previously reported that the pleckstrin homology (PH) domain of Bruton's tyrosine kinase (Btk) binds Ins(1,3,4,5)P4 and that missense mutations in this domain which cause either human X-linked agammaglobulinemia (XLA) or murine X-linked immunodeficiency (Xid) also dramatically reduce the Ins(1,3,4,5)P4 binding activity. In this paper, we describe the inositol phosphate binding specificity of the Btk PH domain and different inositol polyphosphate binding properties among the PH domains of Tec family kinases. Our results suggest that certain inositol phosphates and/or phosphoinositides are physiological ligands of some Tec family kinases and that Tec family members are differently regulated by inositol molecules.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed1997

Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP.

Distinct inositol and phosphatidylinositol polyphosphates 5-phosphatases have recently been cloned. Primers have been designed coding for highly conserved amino acid regions that are shared between sequences of 5-phosphatases. One of the PCR fragment referred to as 51 C, shows 99% identity to a previously reported sequence (INPPL-1) present in the database. We report here the identification of cDNAs for a new SH2-domain-containing protein showing homology to the inositol 5-phosphatase SHIP and therefore referred to as SHIP2. SHIP2 differs at both N- and C-terminal ends with the sequence of INPPL-1. The translated sequence of SHIP2 encodes a 1258 amino acid protein with a predicted molecular mass of 142 kDa. Particularly high levels of SHIP2 were found in human heart, skeletal muscle and placenta as shown by Northern blot analysis. SHIP2 was also expressed in dog thyroid cells in primary culture where the expression was enhanced in TSH and EGF-stimulated cells.

Amino Acid Sequence↗

PubMed1997

Regulation of AP-2-synaptotagmin interaction by inositol high polyphosphates.

The inositol high-polyphosphate series (IHPS) inhibits neurotransmission through binding to the second C2 domain of synaptotagmins I and II(Syt), synaptic vesicle membrane proteins. We have revealed that several proteins, including alpha adaptins which are specific subunits of clathrin assembly protein, AP2, were eluted from mouse brain by affinity elution chromatography from the C2 domains of Syt II-immobilized Sepharose using 50 microM of InsP6. The interaction between Syt II and AP2 was more markedly inhibited by IHPS than by the same concentration of InsP3. Limited digestion of mouse crude synaptosomal fractions with trypsin revealed different cleavage patterns in the presence and absence of 50 microM InsP6. These results suggest that IHPS-binding to the C2B domain of synaptotagmin alters the state of protein-protein interaction including the synaptotagmin-AP2 interaction, possibly resulting in the inhibition of events involved in the synaptic vesicle trafficking.

Adaptor Protein Complex 2↗

PubMed1998

Attenuation of LPA-mediated calcium signaling and inositol polyphosphate production in rat-1 fibroblasts transformed by the v-src oncogene.

Alterations in cellular signaling underlie the transforming actions of many oncogenes. The vsrc oncogene tyrosine kinase, pp60vsrc, is known to alter multiple signal transduction pathways, including those involving phosphatidylinositol (PI) metabolism. In this study, we investigated the effects of vsrc-transformation on lysophosphatidic acid (LPA) receptor coupling to intracellular free calcium [Ca2+]i and PI turnover in rat-1 fibroblasts. In normal rat-1 cells, LPA rapidly elevated [Ca2+]i (EC50 = 10nM). In contrast, the ability of LPA to mobilize calcium was markedly attenuated in rat-1-vsrc cells. Further study revealed that the LPA-mediated generation of inositol (1,4,5)P3 and other inositol polyphosphates was also markedly attenuated in the vsrc-transformed cells. Although LPA caused a transient reduction in the level of PI(4,5)P2 in normal rat-1 cells, the agonist elevated the level of PI(4,5)P2 in the vsrc-transformed cells. These findings demonstrate that vsrc-transformation alters the coupling of LPA receptors to PI turnover and calcium signaling in rat-1 cells, and point to G protein-coupled receptor systems as targets for modulation by the vsrc kinase.

Calcium↗

PubMed1995

Effect of lindane exposure on rainbow trout (Oncorhynchus mykiss) immunity. IV. Prevention of nonspecific and specific immunosuppression by dietary vitamin C (ascorbate-2-polyphosphate).

The effect of the organochlorine insecticide lindane (gamma-hexachlorocyclohexane) administered intraperitoneally at 10 or 50 mg/kg body wt on some major immune functions of rainbow trout (Oncorhynchus mykiss) was examined. Fish were fed vitamin C as ascorbate-2-polyphosphate at a basal level (60 mg ascorbic acid-(AA)-equivalent/kg of feed) or a high level (2000 mg AA-equivalent/kg) 1 month before lindane exposure and during the whole experiment. The aim of the experiment was to determine whether dietary vitamin C is able to prevent immunosuppression due to lindane. The concentration of ascorbic acid in organs and the circulation was controlled, and the number of lindane residues in whole body was measured by gas chromatography. Nonspecific immune response was investigated through the determination of sera lysozyme and ceruloplasmin; both were significantly modified by lindane exposure while the immediate stimulating effects of vitamin C were observed. Cellular immunity was investigated by determining the number of B lymphocytes (analyzed by cytofluorometry) and their ability to proliferate with mitogens. One month after exposure to lindane (10 mg/kg) the proportion of Ig+ lymphocytes in head kidney was significantly decreased by the insecticide. Higher levels of vitamin C (2000 mg/kg) led to a significant increase in this parameter. Thus, vitamin C had a compensating effect on the number of Ig+ lymphocytes in exposed fish. Lindane at 10 mg/kg decreased the proliferation of B lymphocytes, but this was not confirmed at 50 mg/kg. Vitamin C stimulated the proliferation for the latter concentration after 2 months of intake. In lindane-exposed fish, the PMA-induced chemiluminescent response of head kidney phagocytic cells was variable from one assay to another, while most of the time vitamin C acted as a stimulant. The humoral response to Yersinia ruckeri was not modified by lindane but was significantly increased by vitamin C for 1 month after the antigen injection and thus 2 months after vitamin intake.

Animals↗

PubMed1976

Cyclic condensed metaphosphates and linear polyphosphates in brown and red algae.

The occurrence of linear condensed polyphosphates and cyclic condensed metaphosphates was studied by means of pulse-labeling with 32P-orthophosphate (3--5h) in a number of Phaeophyceae species: Pylaiella litoralis, Ilea fascia, Ectocarpus siliculosus and also Rhodophyceae species: Ceramiumdeslongchampsii, C. rubrum, Rhodomela confervoides, Porphyridium purpureum and P. aerugineum. Two-dimensional cellulose thin layer chromatography revealed that in all species studied 32P-radioactivity was generally present in all oligopolyphosphates containing 2 to 7 phosphate residues, in cyclic metaphosphates (tri-, tetra-, penta- and hexametaphosphates) and in high-molecular-weight condensed phosphates which remained at the starting point. Among the low-molecular-weight condensed inorganic phosphates the trimetaphosphate had a significantly higher specific activity than the other oligophosphates which were separated on the chromatography plates as measured by the direct scanning with a Geiger-Muller counter. The phosphate uptake strongly depends on the internal pool of reserve phosphates of the algae cells. The 32P-orthophosphate incorporation of the cells is low and sluggish when growning in a synthetic medium or in sea water. Accordingly 32P appeared preferentially in the low-molecular-weight fractions of condensed phosphates since the storage phosphates were not yet used. After previous incubation in a P-free culture medium of the algae the 32P was rather rapidly incorporated and was found mostly in the high-molecular-weight condensed phosphates. During MAK-chromatography the high-molecular-weight fractions were eluted together with the nucleic acids (tRNA and DNA) while most of the low-molecular-weight fractions left the column immediately on elution.

Eukaryota↗

PubMed1975

Prebiotic peptide-formation in the solid state. III. Condensation reactions of glycine in solid state mixtures containing inorganic polyphosphates.

The reactions of glycine with inorganic polyphosphates in the solid state have been studied. The formation of peptides up to the decamer occurs at moderate temperatures(r.t.-100 degrees C) in the presence of imidazole and magnesium chloride. If adenosine 5' -monophosphate is added to the reaction mixture, 2'(3') -o-glycyl adenosine 5'-monophosphate is also obtained. These reactions could have occurred on the primitive earth.

Adenine Nucleotides↗

PubMed1982

Pharmacokinetics of doxycycline polyphosphate after oral multiple dosing in humans.

Nine healthy volunteers received oral multiple doses of doxycycline polyphosphate for 6 days. Three different dosage schedules were given and the time concentration data obtained was used to determine the best protocol for producing effective serum antibiotic levels during a complete period of treatment with the aid of a mathematical simulation programme. This protocol consisted of the administration of a 200 mg loading dose on the first day, followed by a 100 mg maintenance dose every twelve hours. Using this dosage schedule a steady state was obtained on the first day of treatment, 3 mg/l was the maximum serum level reached, and the lowest serum concentration was more than 1 mg/l which was assumed to be a therapeutically effective serum concentration.

Administration, Oral↗

PubMed1979

Serum kinetics of doxycycline polyphosphate in dogs.

Serum kinetics of Doxycycline polyphosphate (DPP) have been studied in dogs after oral administration of 10 mg.kg-1 by measurement of total serum concentration (Ct) of tetracycline derivatives by a chemical assay and active concentration (Ca) by a microbiological method. Kinetics have been studied using a one compartment open model with absorption by oral route. DPP is rapidly absorbed, the peak serum level is reached three hours after absorption and slowly eliminated (elimination half-life = 12 hours). The main differences observed between Ct and Ca kinetics are in the values of the areas under the curves (AUC) and the peak serum level. The values obtained for these parameters for Ca kinetics were found to be 50% of those obtained for Ct, the volumes of distribution being in inverse proportion. These results are in a good agreement with the correlation and linear regression observed between Ca and Ct showing that 55% of total serum Doxycycline possesses immediate antibacterial activity. It is postulated that this difference between Ct and Ca kinetics is essentially a reflection of the ratios of bound and free drug. Similar results were obtained with the finished pharmaceutical form except for a 15% increase of AUC indicating improvement of the bioavailability of the drug.

Animals↗

PubMed1983

Pharmacokinetic study of doxycycline polyphosphate+ after simultaneous ingestion of milk.

Pharmacokinetic parameters of doxycycline polyphosphate were studied in healthy volunteers after oral administration of a single 200 mg dose of this antibiotic with a breakfast containing or not 200 ml of whole milk. Ingestion of milk had only mild effect upon absorption parameters of doxycycline; only a moderate increase of the lag-time was significant. Elimination parameters of doxycycline were impaired by milk; a decrease of the terminal half-life from 28 h to 15 h, and apparent decrease of the enterohepatic circulation and an increase in total body clearance from 40 to 62 ml/min. were observed.

Adult↗

PubMedDate not supplied

Pharmacokinetics and tissue localization of doxycycline polyphosphate and doxycycline hydrochloride in the rat.

Two doxycycline derivatives Doxycycline polyphosphate and Doxycycline hydrochloride were administered to rats at a dose of 20 mg/kg body weight. Doxycycline tissue levels were determined using a microbiological assay. Only an insignificant fraction of the antibiotics was found to cross the blood brain barrier. Doxycycline was highly concentrated in excretory organs: liver, kidneys and caecum. The high intestinal drug level observed is probably related to the entero-hepatic cycle of this antibiotic. There was a good correlation between serum and heart doxycycline concentration; heart level was about twice that of serum. In lung, antibiotic level was always higher than in serum.

Animals↗

PubMed2005

Prior vasorelaxation enhances diadenosine polyphosphate-induced contractility of rat mesenteric resistance arteries.

Low-threshold concentrations of diadenosine polyphosphates (ApnA: Ap3A, Ap4A, Ap5A, Ap6A) or ATP, which at basal vessel tone induce just measurable vasoconstrictions, induce up to ten times enhanced vasoconstrictions of previously relaxed (by acetylcholine or sodium nitroprusside or 8Br2 cGMP or isoproterenol or levcromakalim) pre-contracted rat mesenteric resistance arteries (MrA) in a microvessel-myograph. These enhanced vasoconstrictions were of similar magnitude for threshold concentrations of all ApnA.Possibly, the low concentrations of ApnA reverse the prior vasorelaxation by inhibiting a common vasorelaxation pathway, but obviously this is not due to inhibition of guanylate cyclase, which has been previously described to be inhibited by ApnA, because the enhanced vasoconstrictions can be observed with guanylate cyclase-independent vasorelaxants (8Br2 cGMP, isoproterenol or levcromakalim), too. The enhanced vasoconstrictions are endothelium-independent because after mechanical vascular de-endothelialization the results were identical. De-endothelialized vessels, which fail to relax by acetylcholine, showed no enhanced ApnA-induced vasoconstrictions, demonstrating that the mere prior vasorelaxation of the vessel is required to provide the enhanced vasoconstriction by ApnA. Furthermore, the enhanced contractility is not based on a potentiation of the phenylephrine contraction because it equally occurs with other agents used for arterial pre-contraction. Systemically applied ApnA considerably decrease arteriovascular resistance, resulting in hypotension. But here it is demonstrated that a preceding vasorelaxation enables the resistance arteries to generate a strong and persistent ApnA-induced vasoconstriction. Thus, in vivo at very low concentrations ApnA may serve to counteract severe conditions of hypotension (e.g., shock syndrome or anaphylaxis) by the constriction of resistance arteries.

Animals↗

PubMed2002

Thermostable Pyrococcus furiosus DNA ligase catalyzes the synthesis of (di)nucleoside polyphosphates.

DNA ligase from the hyperthermophilic marine archaeon Pyrococcus furiosus (Pfu DNA ligase) synthesizes adenosine 5'-tetraphosphate (p4A) and dinucleoside polyphosphates by displacement of the adenosine 5'-monophosphate (AMP) from the Pfu DNA ligase-AMP (E-AMP) complex with tripolyphosphate (P3), nucleoside triphosphates (NTP), or nucleoside diphosphates (NDP). The experiments were performed in the presence of 1-2 microM [alpha-32P]ATP and millimolar concentrations of NTP or NDP. Relative rates of synthesis (%) of the following adenosine(5')tetraphospho(5')nucleosides (Ap4N) were observed: Ap4guanosine (Ap4G) (from GTP, 100); Ap4deoxythymidine (Ap4dT) (from dTTP, 95); Ap4xanthosine (Ap4X) (from XTP, 94); Ap4deoxycytidine (Ap4dC) (from dCTP, 64); Ap4cytidine (Ap4C) (from CTP, 60); Ap4deoxyguanosine (Ap4dG) (from dGTP, 58); Ap4uridine (Ap4U) (from UTP, <3). The relative rate of synthesis (%) of adenosine(5')triphospho(5')nucleosides (Ap3N) were: Ap3guanosine (Ap3G) (from GDP, 100); Ap3xanthosine (Ap3X) (from XDP, 110); Ap3cytidine (Ap3C) (from CDP, 42); Ap3adenosine (Ap3A) (from ADP, <1). In general, the rate of synthesis of Ap4N was double that of the corresponding Ap3N. The enzyme presented optimum activity at a pH value of 7.2-7.5, in the presence of 4 mM Mg2+, and at 70 degrees C. The apparent Km values for ATP and GTP in the synthesis of Ap4G were about 0.001 and 0.4mM, respectively, lower values than those described for other DNA or RNA ligases. Pfu DNA ligase is used in the ligase chain reaction (LCR) and some of the reactions here reported [in particular the synthesis of Ap4adenosine (Ap4A)] could take place during the course of that reaction.

Adenosine Monophosphate↗

PubMed1992

Extracellular hydrolysis of diadenosine polyphosphates, ApnA, by bovine chromaffin cells in culture.

An ectoenzyme hydrolyzing diadenosine polyphosphates (ApnA) to AMP and Ap(n-1) has been studied in cultured chromaffin cells from bovine adrenal medulla. The KM value for extracellular Ap4A hydrolysis was 2.90 +/- 0.72 microM, the V(max) value obtained was 11.59 +/- 0.92 pmol/min x 10(6) cells (116 pmol/min.mg total protein). Ap3A, Ap5A, Ap6A, and Gp4G were competitive inhibitors of Ap4A hydrolysis with K(i) values of 3.65, 1.10, 1.20, and 2.65 microM, respectively. Phosphatidylinositol-specific phospholipase C removes the ApnA hydrolase activity from cultured chromaffin cells, suggesting an anchorage of this protein to the plasma membrane through the phosphatidylinositol. The turnover time for this enzyme calculated in the presence of cycloheximide was 38.94 +/- 1.53 hr for cultured chromaffin cells.

Acid Anhydride Hydrolases↗

PubMed1987

Angiotensin-induced formation and metabolism of inositol polyphosphates in bovine adrenal glomerulosa cells.

The actions of angiotensin II (AII) on inositol polyphosphate production and metabolism were analyzed in cultured bovine adrenal glomerulosa cells. In cells labeled for 24 hr with [3H]inositol, AII caused a rapid and prominent rise in formation of Ins-P3 (mainly the Ins-1,3,4,-P3 isomer) and of Ins-P4, with marked increases in two isomers of Ins-P2 and Ins-P. These findings are consistent with rapid formation and turnover of Ins-1,4,5-P3, partly via conversion to Ins-1,3,4,5-P4 with subsequent metabolism to Ins-1,3,4-P3 and lower inositol phosphates. The demonstration of a cytosolic Ins-P3-kinase gave further evidence for the presence of the tris/tetrakisphosphate pathway and Ins-P4 synthesis during AII action in the bovine adrenal cortex.

Adrenal Cortex↗

PubMed1988

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

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

Animals↗

PubMed1981

The structural conformation of the polyphosphate chain of the ATP molecule is critical for its promotion of prostaglandin biosynthesis.

The adenine nucleotide ATP relaxed the tracheal strip of the guinea pig, while the methylene isosteres of ATP, alpha, beta-methylene ATP (APCPP) and beta, gamma-methylene ATP (APPCP) in concentrations up to 100 micrograms were either inactive or produced a small contraction. The relaxation of the tracheal strip elicited by ATP was completely abolished by treatment of the tissue with indomethacin, a prostaglandin synthesis inhibitor. The relaxations induced by ATP in the guinea-pig taenia coli were followed by a rebound contraction which could be blocked by indomethacin. The two methylene analogues of ATP, produced relaxations in the taenia coli which were not followed by a rebound contraction. It is concluded that in the guinea-pig tracheal chain and taenia coli preparations ATP stimulated prostaglandin synthesis while the analogues modified in the polyphosphate chain were unable to do so.

Adenosine Triphosphate↗

PubMed1981

The time course of 99Tcm-Sn-polyphosphate scintimetry of normally healing tibial fractures in man.

In 38 fractures of the human tibia showing radiological consolidation within 6 months, the amount of callus formed was assessed monthly by scintimetry following intravenous administration of 99Tcm-Sn-polyphosphate. The results of the scintimetry were expressed as a ratio (as radioactivity over the fracture divided by that over the contralateral area of the normal leg). The error of the scintimetric ratio within the period of measurements (20-60 minutes after the injection of isotope) was +/- 5 per cent. More isotope accumulated around the fracture in all patients. The scintimetric time course of transverse as well as longitudinal fractures showed a peak value (scintimetric ratio 3.6 +/- 0.6 s.d.) in the fourth to fifth week, whatever the primary treatment, and was of the same magnitude in the two types of fracture. A secondary increase of the scintimetric ratio was found in 70 per cent of the fractures following the start of weight bearing. Infection of a fracture induced a higher scintimetric ratio than that of an uninfected fracture. Re-fractures showed exceptionally high scintimetric ratios in the second to fourth week (twice the values of primary fractures), but the ratios decreased rapidly. Scintimetry is non-invasive, quantitative method of estimating the formation of callus. In this study the scintimetric time course of healing fractures of the tibia was determined. The results are to serve as a basic study of the method's suitability in early diagnosis of pathological healing.

Adolescent↗