Evidence that inositol 1-phosphate in brain of lithium-treated rats results mainly from phosphatidylinositol metabolism

Ackermann, Karen; Gish, Beverly G.; Honchar, Michael P.; Sherman, William R.

doi:10.1042/bj2420517

Cited by 121 publications

(83 citation statements)

References 30 publications

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“…This agrees with previous reports in which Ins(4)P was shown to be the predominant inositol monophosphate formed [33][34][35]. However, there are also reports of the production of Ins(l)P or mixtures of Ins(l)P and Ins(4)P in which Ins(l)P is the predominant form [36,37]. However, this could be explained by the fact that Siess [37] used whole platelets stimulated with thrombin or vasopressin, whereas in the other study inositol monophosphates were measured in a different tissue, calf brain.…”

Section: Discussionsupporting

confidence: 92%

Subcellular localization of the enzymes that dephosphorylate myo-inositol polyphosphates in human platelets

Vedia

Nolan

Lapetina

1988

Biochemical Journal

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The phosphatase-induced hydrolysis of [3H]inositol 1,4-bisphosphate [Ins(1,4)P2)] and [3H]inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] was studied in platelet subcellular fractions. The activity that hydrolyses Ins(1,4)P2 is cytosolic, whereas the activity that hydrolyses Ins(1,4,5)P3 is present in both particulate and cytosolic fractions. The cytosolic Ins(1,4)P2 phosphatase hydrolyses the 1-phosphate of Ins(1,4)P2, whereas the cytosolic and membrane-bound Ins(1,4,5)P3 phosphatases hydrolyse the 5-phosphate of Ins(1,4,5)P3. In the presence of ATP, it is possible to observe a cytosolic Ins(1,4,5)P3 3-kinase that phosphorylates Ins(1,4,5)P3 to inositol 1,3,4,5-tetrakisphosphate. Apparent Km values for the particulate and the cytosolic Ins(1,4,5)P3 phosphatases are 100 tM and 40,/M respectively. A large proportion of the membraneassociated Ins(1,4,5)P3 phosphatase can be extracted with 1 M-NaCl, and the Mr of this enzyme, as determined by hydrodynamic studies, is 49000, whereas that of the cytosolic enzyme is 59000. The Km values for the cytosolic Ins(1,4)P2 phosphatase is 40 ,UM; this enzyme has an Mr of49 000. The highest specific activity of the Ins(1,4,5)P3 phosphatase is present in a highly purified plasma-membrane fraction.

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Section: Discussionsupporting

confidence: 92%

Subcellular localization of the enzymes that dephosphorylate myo-inositol polyphosphates in human platelets

Vedia

Nolan

Lapetina

1988

Biochemical Journal

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“…To measure the sensitivities ofIns(4,5)P2 dephosphorylation to Li' and 2,3-bisphosphoglycerate, we synthesized and purified [2-3H] (Eisenberg, 1967;Hallcher & Sherman, 1980;-Ackermann et al, 1987 In Dictyostelium homogenates, L-InslP and Ins4P are dephosphorylated under conditions similar to those described for the above systems. Li' inhibits the dephosphorylation of L-[U-'4C]InslP in the soluble fraction of these homogenates, with half-maximal inhibition at about 2.5 mm (Fig 7).…”

Section: Homogenatementioning

confidence: 99%

“…In the best studied mammalian systems, such as human erythrocytes, platelets, rat brain, liver, pancreas and parotid gland, the Ins(1,4,5)P3 response is attenuated by a specific phosphatase which removes the phosphate from the 5-position to yield Ins(1,4)P2 (Downes et al, 1982;Storey et al, 1984;Connolly et al, 1985;Erneux et al, 1986;Shears et al, 1987). Ins(1,4)P2 is then further dephosphorylated to Ins4P in rat liver and brain and calf brain (Delvaux et al, 1987a;Ackermann et al, 1987;Ragan et al, 1988), and finally to Ins. The Ins formed in this way can then be re-used for the synthesis of inositol phospholipids, thus closing the cyclic metabolic pathway characteristic for this signalling system.…”

Section: Introductionmentioning

confidence: 99%

Two dephosphorylation pathways of inositol 1,4,5-trisphosphate in homogenates of the cellular slime mould Dictyostelium discoideum

Campagne

Erneux²,

Eijk

et al. 1988

Biochemical Journal

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Dictyostelium discoideum homogenates contain phosphatase activity which rapidly dephosphorylates Ins(1,4,5)P3 (D-myo-inositol 1,4,5-trisphosphate) to Ins (myo-inositol). When assayed in Mg2", Ins(1,4,5)P3 is dephosphorylated by the soluble Dictyostelium cell fraction to 20% Ins(1,4)P2 (D-myo-inositol 1,4-bisphosphate) and 80 % Ins(4,5)P2 (D-myo-inositol 4,5-bisphosphate). In the particulate fraction Ins(1,4,5)P, 5-phosphatase is relatively more active than the Ins(1,4,5)P3 1-phosphatase. CaCl2 can replace MgCl2 only for the Ins(1,4,5)P3 5-phosphatase activity. Ins(1,4)P2 and Ins(4,5)P2 are both further dephosphorylated to Ins4P (D-myo-inositol 4-monophosphate), and ultimately to Ins. Li' ions inhibit Ins(1,4,5)P3 l-phosphatase, Ins(1,4)P2 1 -phosphatase, Ins4P phosphatase and L-Ins1 P (L-myo-inositol 1 -monophosphate) phosphatase activities; Ins(1,4,5)P3 I-phosphatase is 10-fold more sensitive to Li' (half-maximal inhibition at about 0.25 mM) than are the other phosphatases (half-maximal inhibition at about 2.5 mM). Ins(1,4,5)P3 5-phosphatase activity is potently inhibited by 2,3-bisphosphoglycerate (half-maximal inhibition at 3 /tM).Furthermore, 2,3-bisphosphoglycerate also inhibits dephosphorylation of Ins(4,5)P2. These characteristics point to a number of similarities between Dictyostelium phospho-inositol phosphatases and those from higher organisms. The presence of an hitherto undescribed Ins(1,4,5)P3 1-phosphatase, however, causes the formation of a different inositol bisphosphatase isomer [Ins(4,5)P2] from that found in higher organisms [Ins(1,4)P2]. The high sensitivity of some of these phosphatases for Li' suggests that they may be the targets for Li' during the alteration of cell pattern by Li' in Dictyostelium.

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“…It is unclear whether this represents a difference among species or whether the investigators were unable to resolve Ins 4P and Pi on the Dowex chromatography system used. Finally, Ackermann et al (26) incubated 700 ,uM Ins(1,4)P2 with crude rat brain cytosol and detected formation of both Ins 4P and Ins 1P, though Ins 4P was the major product. The difference between this result and the data presented here might result from action of a 4-phosphatase with low affinity for Ins(1,4)P2 that we were unable to detect at low substrate concentrations.…”

mentioning

confidence: 99%

Pathway for inositol 1,3,4-trisphosphate and 1,4-bisphosphate metabolism.

Inhorn¹,

Bansal²,

Majerus³

1987

Proc. Natl. Acad. Sci. U.S.A.

109

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We prepared [3H]inositol-, 3-[32P]phosphateand 4-[32P]phosphate-labeled inositol phosphate substrates to investigate the metabolism of inositol 1,3,4-trisphosphate and inositol 1,4-bisphosphate. In crude extracts of calf brain, inositol 1,3,4-trisphosphate is first converted to inositol 3,4-bisphosphate, then the inositol 3,4-bisphosphate intermediate is further converted to inositol 3-phosphate. Similarly, inositol 1,4-bisphosphate is converted to inositol 4-phosphate, and no inositol 1-phosphate is formed. We partially purified an enzyme that we tentatively name inositol polyphosphate 1-phosphatase. This cytosolic enzyme converts inositol 1,3,4-trisphosphate to inositol 3,4-bisphosphate and also converts inositol 1,4-bisphosphate to inositol 4-phosphate. The enzyme does not utilize inositol 1,3,4,5-tetrakisphosphate, inositol 1,4,5-trisphosphate, or inositol 1-phosphate as substrates.Thus we propose a new scheme for inositol phosphate metabolism. According to this pathway inositol 1,4,5-trisphosphate and inositol 1,4-bisphosphate are degraded to inositol 4-phosphate. Inositol 1-phosphate, which is the major inositol monophosphate formed in stimulated brain, is derived either from phospholipase C cleavage of phosphatidylinositol or from the degradation of inositol cyclic phosphates.Inositol phospholipids are membrane lipids that are rapidly metabolized in response to extracellular agonists to liberate several second messenger molecules and precursors of messenger molecules (for review, see refs. 1-3). A phospholipase C enzyme hydrolyzes all three inositol phospholipids (4) to yield mixtures of cyclic and noncyclic phosphate esters (5-7), namely, inositol 1-phosphate (Ins 1P), inositol 1,4-bisphosphate [Ins(1,4)P2], inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], and the (1:2) cyclic counterparts of each. The metabolism of the water-soluble inositol phosphates is complex. An inositol phosphate 5-phosphomonoesterase converts Ins(1,4,5)P3 and its cyclic counterpart to Ins(1,4)P2 (8-10) and cyclic inositol 1:2,4-bisphosphate (11), respectively. Additionally, Ins(1,4,5)P3 is metabolized to inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] by a 3-kinase and subsequently converted to a different inositol trisphosphate isomer, inositol 1,3,4-trisphosphate [Ins(1,3,4)P3], by the same 5-phosphomonoesterase (12-17).In the current study, we have investigated the further metabolism of Ins(1,3,4)P3 in crude extracts from calf brain utilizing substrates with radiolabels in the inositol ring, the 3-phosphate, or the 4-phosphate. We find that inositol 3,4-bisphosphate [Ins(3,4)P2] is the first product formed from Ins(1,3,4)P3. In addition, we find that the enzyme that utilizes this substrate also converts Ins(1,4)P2 to inositol 4-phosphate (Ins 4P). Based on these results, a new pathway for inositol phosphate metabolism is proposed. (21). Dowex Chromatography of Inositol Phosphates. Reaction mixtures were diluted to 1 ml with H20 containing 50 nmol Pi and poured onto a 1.5 x 11 cm Dowex-formate column equilibrated in 50...

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Evidence that inositol 1-phosphate in brain of lithium-treated rats results mainly from phosphatidylinositol metabolism

Cited by 121 publications

References 30 publications

Subcellular localization of the enzymes that dephosphorylate myo-inositol polyphosphates in human platelets

Subcellular localization of the enzymes that dephosphorylate myo-inositol polyphosphates in human platelets

Two dephosphorylation pathways of inositol 1,4,5-trisphosphate in homogenates of the cellular slime mould Dictyostelium discoideum

Pathway for inositol 1,3,4-trisphosphate and 1,4-bisphosphate metabolism.

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