Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Epi-inositol regulates expression of the yeast INO1 gene encoding inositol-1-P synthase

Molecular Psychiatry volume 7, pages 174–180 (2002)Cite this article

Abstract

Myo-inositol exerts behavioral effects in animal models of psychiatric disorders and is effective in clinical trials in psychiatric patients. Interestingly, epi-inositol exerts behavioral effects similar to myo-inositol, even though epi-inositol is not a substrate for synthesis of phosphatidylinositol. We postulated that the behavioral effects of epi-inositol may be due to its effects on gene expression. Yeast INO1expression was measured in northern blots. INM1 was determined by β-galactosidase activity in a strain containing the fusion gene INM1-lacZintegrated into the genome. Epi-inositol affects regulation of expression of the INO1 gene (encoding inositol-1-P synthase), even though it cannot support growth of an inositol auxotroph (suggesting that, as in mammalian cells, it is not incorporated into phosphatidylinositol). Like myo-inositol, although to a lesser extent, epi-inositol causes a significant reduction in INO1 expression, and reverses the lithium- or valproate-induced increase in INO1 expression. However, it does not affect regulation of INM1 (encoding inositol monophosphatase), the expression of which is up-regulated by myo-inositol. The observed regulatory effects of epi-inositol on expression of the most highly regulated gene in the inositol biosynthetic pathway may help to explain how this inositol isomer can exert behavioral effects without being incorporated into phosphatidylinositol.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. De Camilli P, Emr SD, McPherson PS, Novick P . Phosphoinositides as regulators in membrane traffic Science 1996 271: 1533–1539

    Article  CAS  Google Scholar 

  2. Parthasarathy R, Eisenberg F . The inositol phospholipids: a sterochemical view of biological activity Biochem J 1986 235: 313–322

    Article  CAS  Google Scholar 

  3. Berridge M . Phosphoinositides and signal transduction Rev Clin Basic Pharm 1985 5 Suppl: 5–13

    Google Scholar 

  4. Rouser G, Kritchevsky G, Yamanoto A, Baxter CF . Lipids in the nervous system of different species as a function of age: brain, spinal cord, peripheral nerve purified whole cell preparations, and subcellular particulates: regulatory mechanisms and membrane structure Adv Lipid Res 1972 10: 261–360

    Article  CAS  Google Scholar 

  5. Wood AJ, Goodwin GM . A review of the biochemical and neuropharmacological actions of lithium Psychol Med 1987 17: 579–600

    Article  CAS  Google Scholar 

  6. Hallcher LM, Sherman WR . The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain J Biol Chem 1980 255: 10896–10901

    CAS  PubMed  Google Scholar 

  7. Belmaker RH, Kofman O . Lithium research: state of the art [editorial] Biol Psychiatry 1990 15: 1279–1281

    Article  Google Scholar 

  8. Manji HK, Lenox RH . Lithium: a molecular transducer of mood-stabilization in the treatment of bipolar disorder Neuropsychopharmacology 1998 3: 161–166

    Google Scholar 

  9. Benjamins JA, Agranoff BW . Distribution and properties of CDP-diglyceride:inositol transferase from brain J Neurochem 1969 4: 513–527

    Article  Google Scholar 

  10. Becchetti A, Whitaker M . Lithium blocks cell cycle transition in the first cell cycles of sea urchin embryos, an effect rescued by myo-inositol Development 1997 124: 1099–1107

    CAS  PubMed  Google Scholar 

  11. Busa WB, Gimlich RL . Lithium-induced teratogenesis in frog embryos prevented by a polyphosphoinositide cycle intermediate or a diacylglycerol analog Dev Biol 1989 132: 315–324

    Article  CAS  Google Scholar 

  12. Mason R, Biello SM . A neurophysiological study of a lithium-sensitive phosphoinositide system in the hamster suprachiasmic (SCN) biological clock in vitro Neurosci Lett 1992 144: 135–138

    Article  CAS  Google Scholar 

  13. Richards MH, Belmaker RH . Epi-inositol is biochemically active in reversing lithium effect on CMP-PA J Neural Transm 1996 103: 1281–1285

    Article  CAS  Google Scholar 

  14. Williams MB, Jope RS . Modulation by inositol of cholinergic- and serotonergic-induced seizures in lithium-treated rats Brain Res 1995 685: 169–178

    Article  CAS  Google Scholar 

  15. Einat H, Elkabaz-Shwortz Z, Cohen H, Kofman O . Chronic epi-inositol has an anxiolytic-like effect in the plus-maze model in rats Int J Neuropsychopharm 1998 1: 31–34

    Article  CAS  Google Scholar 

  16. Patishi Y, Belmaker RH, Bersudsky Y, Kofman O . A comparison of the ability of myo-inositol and epi-inositol to attenuate lithium-pilocarpine seizures in rats Biol Psychiat 1996 39: 829–832

    Article  CAS  Google Scholar 

  17. Godfrey PP . Potentiation by lithium of CMP-phosphatidate formation in carbachol-stimulated rat cerebral-cortical slices and its reversal by myo-inositol Biochem J 1989 258: 621–624

    Article  CAS  Google Scholar 

  18. Levine J, Barak Y, Gonsalves M, Elizur A, Schor H, Kofman O, Belmaker RH . Double blind study of inositol versus placebo in depression Am J Psychiatry 1995 152: 792–794

    Article  CAS  Google Scholar 

  19. Benjamin J, Levine J, Fux M, Aviv A, Levy D, Belmaker RH . Double blind controlled trial of inositol treatment of panic disorder Am J Psychiatry 1995 152: 1084–1086

    Article  CAS  Google Scholar 

  20. Cohen H, Kotler M, Kaplan Z, Matar MA, Kofman O, Belmaker RH . Inositol has centrally-mediated behavioral effects with adaptation after chronic administration J Neural Transm 1997 104: 299–305

    Article  CAS  Google Scholar 

  21. Einat H, Karbovski H, Korik J, Tsalah D, Belmaker RH . Inositol reduces depressive-like behaviors in two different animal models of depression Psychopharmacology 1999 144: 158–162

    Article  CAS  Google Scholar 

  22. Einat H, Shaldubina A, Belmaker RH . Epi-inositol: a potential antidepressant Drug Devel Res 2000 50: 309–315

    Article  CAS  Google Scholar 

  23. Carman GM, Henry SA . Phospholipid biosynthesis in the yeast Saccharomyces cerevisiae and interrelationship with other metabolic processes Prog Lipid Res 1999 38: 361–399

    Article  CAS  Google Scholar 

  24. Greenberg ML, Lopes JM . Genetic regulation of phospholipid biosynthesis in yeast Microbiol Rev 1996 60: 1–20

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Murray M, Greenberg ML . Expression of yeast INM1 encoding inositol monophosphatase is regulated by inositol, carbon source, and growth stage and is decreased by lithium and valproate Mol Microbiol 2000 36: 651–661

    Article  CAS  Google Scholar 

  26. UniGen Cluster Analysis www.ncbi.nlm.nih.gov/UniGene/clust.cgi

  27. Bennett MK, Scheller RH . The molecular machinery for secretion is conserved from yeast to neurons Proc Natl Acad Sci 1993 90: 2559–2563

    Article  CAS  Google Scholar 

  28. Vaden D, Ding D, Peterson B, Greenberg ML . Lithium and valproic acid decrease inositol mass and increase expression of the INO1 and INO2 genes for inositol biosynthesis in Saccharomyces cerevisiae J Biol Chem 2001 276: 15466–15471

    Article  CAS  Google Scholar 

  29. Murray M, Greenberg ML . Regulation of inositol monophosphatase in Saccharomyces cerevisiae Mol Microbiol 1997 3: 541–546

    Article  Google Scholar 

  30. Ashburner BP, Lopes JM . Regulation of yeast phospholipid biosynthetic gene expression in response to inositol involves two superimposed mechanisms Proc Natl Acad Sci USA 1995 92: 9722–9726

    Article  CAS  Google Scholar 

  31. Hirsch JP, Henry SA . Expression of the Saccharomyces cerevisiae inositol-1-phosphate synthase (INO1) gene is regulated by factors that affect phospholipid synthesis Mol Cell Biol 1986 6: 3320–3328

    Article  CAS  Google Scholar 

  32. Bradford MM . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding Anal Biochem 1976 72: 248–254

    Article  CAS  Google Scholar 

  33. Henry SA, Donahue TF, Culbertson MR . Selection of spontaneous mutants by inositol starvation in yeast Mol Gen Genet 1975 143: 5–11

    Article  CAS  Google Scholar 

  34. Lopez F, Leube M, Gil-Mascarell R, Navarro-Aviñó JP, Serrano R . The yeast inositol monophosphatase is a lithium- and sodium-sensitive enzyme encoded by a non-essential gene pair Mol Microbiol 1999 4: 1255–1264

    Article  Google Scholar 

  35. Patton-Vogt JL, Griac P, Sreenivas A, Bruno V, Dowd S, Swede MJ et al. Role of the yeast phosphatidylinositol/phosphatidylcholine transfer protein (Sec14p) in phosphatidylcholine turnover and INO1 regulation J Biol Chem 1997 272: 20873–20883

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Yuly Bersudsky for editorial and statistical consultation. This work was supported by grant MH56220 (to MLG) from the National Institutes of Health.

Author information

Authors and Affiliations

  1. Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel

    A Shaldubina & R H Belmaker

  2. Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA

    S Ju, D L Vaden, D Ding & M L Greenberg

Authors
  1. A Shaldubina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Ju
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D L Vaden
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R H Belmaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M L Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M L Greenberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shaldubina, A., Ju, S., Vaden, D. et al. Epi-inositol regulates expression of the yeast INO1 gene encoding inositol-1-P synthase. Mol Psychiatry 7, 174–180 (2002). https://doi.org/10.1038/sj.mp.4000965

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000965

Keywords

This article is cited by

Search

Advanced search

Quick links