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:

Altered IMPA2 gene expression and calcium homeostasis in bipolar disorder

Molecular Psychiatry volume 6, pages 678–683 (2001)Cite this article

Abstract

Reduced inositol monophosphatase (IMPase) activity and elevated basal intracellular calcium levels ([Ca2+]B) have been reported in B lymphoblast cell lines (BLCLs) from bipolar I affective disorder (BD-I) patients, which may reflect cellular endophenotypes of this disorder. As the PI cycle couples to intracellular Ca2+ mobilization, these two putative endophenotypes may be related. Using an RT-PCR assay, mRNA levels were estimated for IMPA1 and 2 genes encoding human IMPase 1 and 2, respectively, in BLCLs phenotyped on [Ca2+]B, from patients with a DSM-IV diagnosis of BD-I (n = 12 per phenotype) and from age- and sex-matched healthy subjects (n = 12). IMPA2 mRNA levels were significantly lower in BLCLs from male BD-I patients with high [Ca2+]B (n = 6) compared with healthy male subjects (n = 5) (−52%, P = 0.013), male BD-I patients with normal BLCL [Ca2+]B (n = 8) (−42%, P = 0.003) and female BD-I patients with high [Ca2+]B (n = 6) (−59%, P = 0.0004). A significant negative correlation was observed between IMPA2 mRNA levels and [Ca2+]B in BLCLs from male (P = 0.046), but not female BD-I patients. Sex-dependent differences were also evident in postmortem temporal cortex IMPA2 mRNA levels which, in contrast to BLCLs, were significantly higher in male BD-I subjects compared with male controls (P = 0.025, n = 4/group). Collectively, these observations suggest a potential sex-dependent link between abnormalities in IMPA2 expression and calcium homeostasis in the pathophysiology of BD.

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

Similar content being viewed by others

References

  1. Craddock N, Jones I . Genetics of bipolar disorder J Med Genet 1999 36: 585–594

    Article  CAS  Google Scholar 

  2. Gershon ES, Badner JA, Goldin LR, Sanders AR, Cravchik A, Detera-Wadleigh SD . Closing in on genes for manic-depressive illness and schizophrenia Neuropsychopharmacology 1998 18: 233–242

    Article  CAS  Google Scholar 

  3. Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J . Psychiatric genetics: search for phenotypes Trends Neurosci 1998 21: 102–105

    Article  CAS  Google Scholar 

  4. Emamghoreishi M, Schlichter L, Li PP, Parikh S, Sen J, Kamble A et al. High intracellular calcium concentrations in transformed lymphoblasts from subjects with bipolar I disorder Am J Psychiatry 1997 154: 976–982

    Article  CAS  Google Scholar 

  5. Atack JR . Inositol monophosphatase, the putative therapeutic target for lithium Brain Res Brain Res Rev 1996 22: 183–190

    Article  CAS  Google Scholar 

  6. Shamir A, Ebstein RP, Nemanov L, Zohar A, Belmaker RH, Agam G . Inositol monophosphatase in immortalized lymphoblastoid cell lines indicates susceptibility to bipolar disorder and response to lithium therapy Mol Psychiatry 1998 3: 481–482

    Article  CAS  Google Scholar 

  7. Nemanov L, Ebstein RP, Belmaker RH, Osher Y . Effect of bipolar disorder on lymphocyte inositol monophosphatase mRNA levels Int J Neuropsychopharmacol 1999 2: 25–29

    Article  CAS  Google Scholar 

  8. Berridge MJ, Irvine RF . Inositol trisphosphate, a novel second messenger in cellular signal transduction Nature 1984 312: 315–321

    Article  CAS  Google Scholar 

  9. Fisher SK, Heacock AM, Agranoff BW . Inositol lipids and signal transduction in the nervous system: an update J Neurochem 1992 58: 18–38

    Article  CAS  Google Scholar 

  10. Sjoholt G, Molven A, Lovlie R, Wilcox A, Sikela JM, Steen VM . Genomic structure and chromosomal localization of a human myo-inositol monophosphatase gene (IMPA) Genomics 1997 45: 113–122

    Article  CAS  Google Scholar 

  11. Yoshikawa T, Turner G, Esterling LE, Sanders AR, Detera-Wadleigh SD . A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder Mol Psychiatry 1997 2: 393–397

    Article  CAS  Google Scholar 

  12. Berrettini WH . Genetics of psychiatric disease Annu Rev Med 2000 51: 465–479

    Article  CAS  Google Scholar 

  13. Parthasarathy L, Vadnal RE, Parthasarathy R, Devi CSS . Biochemical and molecular properties of lithium-sensitive myo-inositol monophosphatase Life Sci 1994 54: 1127–1142

    Article  CAS  Google Scholar 

  14. Rahman S, Li PP, Young LT, Kofman O, Kish SJ, Warsh JJ . Reduced [3H]cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder J Neurochem 1997 68: 297–304

    Article  CAS  Google Scholar 

  15. Vogt T, Stolz W, Welsh J, Jung B, Kerbel RS, Kobayashi H et al. Overexpression of Lerk-5/Eplg5 messenger RNA: a novel marker for increased tumorigenicity and metastatic potential in human malignant melanomas Clin Cancer Res 1998 4: 791–797

    CAS  Google Scholar 

  16. Winer BJ . Statistical Principles in Experimental Design, 2nd edn McGraw-Hill Book Co: New York 1971 pp 456–457

    Google Scholar 

  17. Soares JC, Mann JJ . The functional neuroanatomy of mood disorders J Psychiatr Res 1997 31: 393–432

    Article  CAS  Google Scholar 

  18. Li PP, Andreopoulos S, Warsh JJ . Signal transduction abnormalities in bipolar affective disorder. In: Reith MEA (ed) Cerebral Signal Transduction: From First to Fourth Messengers Humana Press: Totowa, New Jersey 2000 pp 283–309

    Chapter  Google Scholar 

  19. Samuelson SD, Winokur G, Pitts AF . Elevated cerebrospinal fluid protein in men with unipolar or bipolar depression Biol Psychiatry 1994 35: 539–544

    Article  CAS  Google Scholar 

  20. Emamghoreishi M, Li PP, Schlichter L, Parikh SV, Cooke R, Warsh JJ . Associated disturbances in calcium homeostasis and G protein-mediated cAMP signaling in bipolar I disorder Biol Psychiatry 2000 48: 665–673

    Article  CAS  Google Scholar 

  21. Yoshikawa T, Padigaru M, Karkera JD, Sharma M, Berrettini WH, Esterling LE et al. Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2) Mol Psychiatry 2000 5: 165–171

    Article  CAS  Google Scholar 

  22. Shimon H, Agam G, Belmaker RH, Hyde TM, Kleinman JE . Reduced frontal cortex inositol levels in postmortem brain of suicide victims and patients with bipolar disorder Am J Psychiatry 1997 154: 1148–1150

    Article  CAS  Google Scholar 

  23. Slusarski DC, Corces VG, Moon RT . Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling Nature 1997 390: 410–413

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Medical Research Council of Canada (JJW) and the National Alliance for Research on Schizophrenia and Affective Disorders (JJW and PPL). The authors thank Mrs Cathy Spegg for advice in performing the statistical analyses.

Author information

Authors and Affiliations

  1. Section of Biochemical Psychiatry, University of Toronto, Toronto, Ontario, Canada

    I-S Yoon, P P Li, K-P Siu & J J Warsh

  2. Section of Neurogenetics, University of Toronto, Toronto, Ontario, Canada

    J L Kennedy

  3. Bipolar Disorders Clinic, Centre for Addiction and Mental Health – Clarke Site, University of Toronto, Toronto, Ontario, Canada

    R G Cooke & S V Parikh

  4. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    I-S Yoon, J L Kennedy & J J Warsh

  5. Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada

    P P Li & J J Warsh

  6. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    P P Li, J L Kennedy, R G Cooke, S V Parikh & J J Warsh

Authors
  1. I-S Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P P Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K-P Siu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J L Kennedy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R G Cooke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S V Parikh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J J Warsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J J Warsh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoon, IS., Li, P., Siu, KP. et al. Altered IMPA2 gene expression and calcium homeostasis in bipolar disorder. Mol Psychiatry 6, 678–683 (2001). https://doi.org/10.1038/sj.mp.4000901

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000901

Keywords

This article is cited by

Search

Advanced search

Quick links