Neurochemical Research

, Volume 25, Issue 7, pp 977–982

A Model of Inositol Compartmentation in Astrocytes Based Upon Efflux Kinetics and Slow Inositol Depletion after Uptake Inhibition

  • Marina Wolfson
  • Yuly Bersudsky
  • Elna Hertz
  • Vladimir Berkin
  • Evgeny Zinger
  • Leif Hertz
Article

Abstract

Intracellular compartmentation of inositol was demonstrated in primary cultures of mouse astrocytes, incubated in isotonic medium, by determination of efflux kinetics after “loading” with [3H]inositol. Three kinetically different compartments were delineated. The largest and most slowly exchanging compartment had a halflife of ∼9 hr. This slow release leads to retention of a sizeable amount of pre-accumulated inositol in the tissue 24 hr after the onset of uptake inhibition, as confirmed by the observation that the inositol uptake inhibitor fucose caused a larger inhibition of unidirectional inositol uptake than of inositol pool size, measured as accumulated [3H]inositol after 24 hr of combined exposure to the inhibitor and the labeled isotope. Based upon the present observations and literature data, it is suggested that the large, slowly exchanging compartment is largely membrane-associated and participating in signaling via the phosphatidylinositide second messenger system, whereas inositol functioning as an osmolyte is distributed in the cytosol and located in one or both of the compartments showing a faster release.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    Chen, Y. and Hertz, L. 1999. Noradrenaline effects on pyruvate decarboxylation-Correlation with calcium signaling. J. Neurosci. Res., 58:599–606.Google Scholar
  2. 2.
    Subbarao, K. V. and Hertz, L. 1990. Effects of adrenergic agonists on glycogenolysis in primary cultures of astrocytes. Brain Res. 527:346–349.Google Scholar
  3. 3.
    Subbarao, K. V. and Hertz, L. 1991. Stimulation of energy metabolism in astrocytes by adrenergic agonists. J. Neurosci. Res. 28:399–405.Google Scholar
  4. 4.
    Hansson, E. and Ronnback, L. 1988. Regulation of glutamate and GABA transport by adrenoceptors in primary astroglial cell cultures. Life Sci. 44:27–34.Google Scholar
  5. 5.
    Alexander, G. M., Grothuse, J. R., Gordon, S. W., and Schwartzman, R. J. 1997. Intracerebral microdialysis study of glutamate reuptake in awake, behaving rats. Brain Res. 766:1–10.Google Scholar
  6. 6.
    Chen, Y., Peng, L., Zhang, X., Stolzenburg, J.-U. and Hertz, L. 1995. Further evidence that fluoxetine interacts with a 5-HT1C receptor. Brain Res. Bull. 38:153–159.Google Scholar
  7. 7.
    Chen, Y., McNeill, J. R., Hajek, I., and Hertz, L. 1992. Effect of vasoprresin on brain swelling at the cellular level–Do astrocytes exhibit a furosemide-vasopressin-sensitive mechanism for volume regulation? Can. J. Physiol. Pharmacol. 70:S367-S373.Google Scholar
  8. 8.
    Chen, Y., Zhao, Z., and Hertz, L. Vasopressin effects on [Ca2+?]i and water permeability in differentiated astrocytes are mediated by potent activation of the V1b/V3 receptor, J. Neurosci. Res., in press.Google Scholar
  9. 9.
    Sarfaraz, D. and C. L. Fraser. 1999. Effects of arginine vasopressin on cell volume regulation in brain astrocytes in culture. Am. J. Physiol. 276 (3Pt. 1):E596-E601.Google Scholar
  10. 10.
    Brinton, R. D., Yamasaki, R., O'Neill, K., Gonzales, C., and Schreiber, S. 1998. Vasopressin induction of the immediate early response gene, NGFI-A in cultured hippocampal glial cells. Mol. Brain Res. 57:73–85.Google Scholar
  11. 11.
    Chen, Y. and Hertz, L. 1996. Inhibition of noradrenaline stimulated increase in [Ca2?]i in astrocytes by chronic treatment with a therapeutically relevant lithium concentration. Brain Res. 711:245–248.Google Scholar
  12. 12.
    Hallcher, L. M. and Sherman, W. R. 1980. The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J. Biol. Chem. 255:10896–10901.Google Scholar
  13. 13.
    Berridge, M. J., Downes, C. P. and Hanley, M. R. 1989. Neural and developmental action of lithium: A unifying hypothesis. Cell 59:411–419.Google Scholar
  14. 14.
    Belmaker, R. H., Agam, G., van Calker, D., Richards, M. H., and Kofman, O. 1998. Behavioral reversal of lithium effects by four inositol isomers correlates perfectly with biochemical effects on the PI cycle; depletion by chronic lithium of brain inositol is specific to hypothalamus, and inositol levels may be abnormal in postmortem brain from bipolar patients. Neuropsychopharmacology 19:220–232.Google Scholar
  15. 15.
    Hertz, L., Wolfson M., Hertz, E., Agam, G., Richards M., and Belmaker, R. H. Lithium/inositol interactions. 1997. in Van Praag, H. M. and Honig A., eds. Depression: Neurobiological, Psychopathological and Therapeutic Advances. Wiley, New York, pp. 519–534.Google Scholar
  16. 16.
    Van Calker, D. and Belmaker, R. H. 1999. The high affinity inositol transport system-Implications for the pathophysiology and treatment of bipolar disorder. Bipolar Disorders, in press.Google Scholar
  17. 17.
    Brand, A., Richter-Landsberg, C. and Leibfritz, D. 1993. Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev. Neurosci. 15:289–298.Google Scholar
  18. 18.
    Lubrich, B. and van Calker, D. 1999. Inhibition of the high-affinity myo-inositol uptake: A common mechanism of action of antibipolar drugs? Neuropsychopharmacology 21:519–529.Google Scholar
  19. 19.
    Wolfson, M., Bersudsky, Y., Zinger E., Simkin, M., Belmaker, R. H., and Hertz, L. 2000. Chronic treatment of human astrocytoma cells with lithium, carbamazepine or valproic acid decreases inositol uptake at high inositol concentrations, but increases it at low inositol concentrations. Brain Res. 855:158–161.Google Scholar
  20. 20.
    Glanville, N. T., Byers, D. M., Cook, H. V., Spence, M. W., and Palmer, F. B.StC. 1989. Differences in the metabolism of inositol and phoshoinositides by cultured cells of neuronal and glial origin. Biochim. Biophys. Acta 1004:69–179.Google Scholar
  21. 21.
    Einat, H., Kofman, O., Itkin, O., Lewitan, R. J., and Belmaker, R. H. 1998. Augmentation of lithium's behavioral effect by inositol uptake inhibitors. J. Neural Transmission 105:31–38.Google Scholar
  22. 22.
    Wolfson, M., Einat, H., Bersudsky, Y., Berkin, V., Belmaker, R. H., and Hertz, L. 1999. Nordidemnin potently inhibits inositol uptake in cultured astrocytes and dose-dependently augments lithium's proconvulsant effect in vivo, J. Neurosci. Res., 60:116–1221.Google Scholar
  23. 23.
    Honchar, M. P., Olney, J. W., and Sherman, W. R. 1983. Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats. Science 220:323–325.Google Scholar
  24. 24.
    Tricklebank, M. D., Singh, L., Jackson, A., and Oles, R. J. 1991. Evidence that a proconvulsant action of lithium is mediated by inhibition of myo-inositol phosphatase in mouse brain. Brain Res. 558:145–148.Google Scholar
  25. 25.
    Kofman, O., Sherman, W. R., Katz, V., and Belmaker, R. H. 1993. Restoration of brain myo-inositol levels in rats increases latency to lithium-pilocarpine seizures. Psychopharmacol. 110:229–234.Google Scholar
  26. 26.
    Bersudsky, Y., Shapiro, J., Agam, G., Kofman, O., and Belmaker, R. H. 1994. Behavioral evidence for the existance of two pools of cellular inositol. Eur Neuropsychopharmacol 4:463–467.Google Scholar
  27. 27.
    Isaacks, R. E., Bender, A. S., Kim, C. Y., Shi, Y. F., and Norenberg, M. D. 1999. Effect of ammonia and methionine sulfoximine on myo-inositol transport in cultured astrocytes. Neurochem. Res. 24:51–59.Google Scholar
  28. 28.
    Isaacks, R. E., Bender, A. S., Kim, C. Y, Shi, Y. F., and Norenberg, M. D. 1999. Effect of osmolality and anion channel inhibitors on myo-inositol efflux in cultured astrocytes. J. Neurosci. Res. 57: 866–871.Google Scholar
  29. 29.
    Yorek, M. A., Dunlap, J. A., Stefani, M. R., and Davidson, E. P. 1992. L-fucose is a potent inhibitor of myo-inositol transport and metabolism in cultured neuroblastoma cells. J. Neurochem. 58:1626–1636.Google Scholar
  30. 30.
    Batty, I. H., and Downes, C. P. 1995. The mechanism of muscarinic receptor-stimulated phosphatidylinositol resynthesis in 1321N1 astrocytoma cells and its inhibition by Li+. J. Neurochem. 65:2279–2289.Google Scholar
  31. 31.
    Wolfson, M., Hertz, E., Belmaker, R. H., and Hertz, L. 1998. Chronic treatment with lithium and pretreatment with excess inositol reduce inositol pool sizes by different mechanisms. Brain Res. 787:34–40.Google Scholar
  32. 32.
    Aukema, H. M. and Holub, B. J. 1994. Inositol and pyrroloquinoline quinone: A: Inositol. in Shils, E, Olson, J. A. and Shike, M. (eds.) Modern Nutrition in Health and Disease, 8th ed. Lea and Febiger, Philadelphia, pp. 466–473.Google Scholar
  33. 33.
    Agam, G., Balfour, N. Shapiro, H., and Belmaker, R. H. 1995. Plasma inositol levels in lithium-treated manic-depressives, schizophrenics and controls. Hum. Psychopharmacol. 10:311–314.Google Scholar
  34. 34.
    Hertz, L., Juurlink, B. H. J., and Szuchet, S. 1985. Cell cultures. in A. Lajtha, A. (ed.) Handbook of Neurochemistry, 2nd Ed., Vol. 8. Plenum Press, New York, pp. 603–661.Google Scholar
  35. 35.
    Juurlink, B. H. J., and Hertz, L. 1992. Astrocytes. in A. A. Boulton, A. A., Baker, G. B., and Walz, W. (eds.) Neuromethods: vol. 23, Cell Cultures, Humana Clifton, NY, pp. 269–321.Google Scholar
  36. 36.
    Hertz, L., Lai, J. C. K., and Peng, L. 1998. Functional studies in cultured astrocytes. Methods-A Companion to Methods in Enzymology 16:293–310.Google Scholar
  37. 37.
    Meier, E., Hertz, L., and Schousboe, A. 1991. Neurotransmitters as developmental signals. Neurochem. Int. 19:1–15.Google Scholar
  38. 38.
    Isaacks, R. E., Bender, A. S., Reuben, J. S., Kim, C. Y., Shi, Y. F., and Norenberg, M. D. 1999. Effect of dibutyryl cyclic AMP on the kinetics of myo-inositol transport in cultured astrocytes. J. Neurochem. 73:105–111.Google Scholar
  39. 39.
    Strange, K., Morrison, R., Heilig, C. W., DiPietro, S., and Gullians, S. R. 1991. Upregulation of inositol transport mediates inositol accumulation in hyperosmolar brain cells. Am. J. Physiol 263 (2Pt1):C412–419.Google Scholar
  40. 42.
    Batty, I. H. and Downes, C. P. 1994. The inhibition of phosphoinositide synthesis and muscarinic-receptor-mediated phospholipase C activity by Li??as secondary, selective, consequences of inositol depletion in 1321N1 cells. Biochem. J. 297:529–537.Google Scholar
  41. 43.
    Batty, I. H., Currie, R. A., and Downes, C. P. 1998. Evidence for a model of integrated inositol phospholipid pools implies an essential role for lipid transport in the maintenance of receptor-mediated phospholipase C activity in 1321N1 cells. Biochem. J. 330:1069–1077.Google Scholar
  42. 44.
    Jackson, P. S. and Strange, K. 1993. Volume-sensitive anion channels mediate swelling-activated inositol and taurine efflux. Am. J. Physiol. 265 (6Pt1):C1489-C1500.Google Scholar

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  • Marina Wolfson
    • 1
  • Yuly Bersudsky
    • 2
  • Elna Hertz
    • 2
  • Vladimir Berkin
    • 2
  • Evgeny Zinger
    • 2
  • Leif Hertz
    • 2
  1. 1.Department of Microbiology and Immunology and Mental Health Center, Faculty of Health SciencesBen Gurion University of the NegevBeer ShevaIsrael
  2. 2.Department of Microbiology and Immunology and Mental Health Center, Faculty of Health SciencesBen Gurion University of the NegevBeer ShevaIsrael

Personalised recommendations