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Lithium and Signal Transduction

  • Shigeru Morinobu
  • Shigeto Yamawaki
  • Takuji Fukumoto
  • Seiichi Tsuji
  • Takami Suenaga
  • Jun Takahashi
  • Kazuhide Tanaka
  • Koichiro Fujimaki
Part of the Advances in Behavioral Biology book series (ABBI, volume 53)

Abstract

Numerous clinical studies have demonstrated that lithium is widely prescribed as a mood stabilizer in the treatment of bipolar mood disorder. An accumulation of evidences, resulted from the pharmacological studies of lithium, postulates several putative actions of this drug.10 These proposed actions include the inhibition of inositol monophosphatase, the modulation of GTP-binding proteins, and the inhibition of glycogen synthase kinase 3ß. These proposed actions are induced in response to an acute administration of lithium. However, since a long-term administration of lithium is required to obtain optimal therapeutic effects, changes in neuronal gene expression that are induced by an activation of transcription factors may be involved in the clinical efficacy of this drug. Numerous molecular pharmacological studies have demonstrated that several signal transduction pathways, such as the β-adrenoceptor-cAMP-protein kinase A or 5-HT2A-calcium (Ca2+)-Ca2+/calmodulin dependent protein kinase II, IV cascade regulate neuronal gene expression through the phosphorylation (activation) of a cAMP response element binding protein (CREB), a major transcription factor in the brain. In this context, the regulation of the expression and phosphorylation of CREB is thought to be an important molecular target of lithium action.

Keywords

cAMP Response Element Binding BDNF mRNA cAMP Response Element Binding Protein PP2A Activity Major Transcription Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    H. Bito, K. Desseroth, and R. W. Tsien, CREB phosphorylation and dephosphorylation: a Ca2+-. and stimulus duration-dependent switch for hippocampal gene expression, Cell 87, 1203–1214 (1996).PubMedCrossRefGoogle Scholar
  2. 2.
    B. Chen, J. F. Wang, B. C. Hill, and L. T. Young, Lithium and valproate differentially regulate brain regional expression of phosphorylated CREB and c-Fos, Brain Res. Mol. Brain Res. 70, 45–53 (1999).PubMedCrossRefGoogle Scholar
  3. 3.
    G. Chen, W-Z. Zeng, P-X. Yuan, L-D. Huang, Y-M. Jiang, Z-H. Zhao, and H. K. Manji, The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS, J. Neurochem. 72, 879–882 (1999).PubMedCrossRefGoogle Scholar
  4. 4.
    R-W. Chen, and D-M. Chuang, Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression, J. Biol. Chem. 274, 6039–6042, 1999.PubMedCrossRefGoogle Scholar
  5. 5.
    K. Fujimaki, S. Morinobu, and R. S. Duman, Administration of a cAMP phosphodiesterase 4 inhibitor enhances antidepressant-induction of BDNF mRNA in rat hippocampus, Neuropsychopharmacol. 22, 42–51 (2000).CrossRefGoogle Scholar
  6. 6.
    T. Fukumoto, S. Morinobu, Y. Okamoto, A. Kagaya, and S. Yamawaki, Chronic lithium treatment increases the expression of brain-derived neurotrophic factor (BDNF) in the rat brain, Psychopharmacol. (in press).Google Scholar
  7. 7.
    G. E. Hardingham, F. J. Arnold, and H. Bading, Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity, Nat. Neurosci. 4, 261–267 (2001).PubMedCrossRefGoogle Scholar
  8. 8.
    A. Ishida, I. Kameshita, and H. Fujisaki, A novel protein phosphatase that dephosphorylates and regulates Ca2+/calmodulin-dependent protein kinase H, J. Biol. Chem. 273, 1904–1910 (1998).PubMedCrossRefGoogle Scholar
  9. 9.
    R. C. Malenka, Synaptic plastisity in the hippocampus, Cell 78, 535–538 (1994).PubMedCrossRefGoogle Scholar
  10. 10.
    H. K. Manji, G. J. Moore, G. Rajikowska, and G. Chen, Neuroplasticity and cellular resilience in mood disorders, Mol. Psychiat. 5, 578–593 (2000).CrossRefGoogle Scholar
  11. 11.
    R. P. Matthews, C. R. Guthrie, L. M. Wailes, X. Zhao, A. R. Means, and G. T. McKnight, Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression. Mol. Cell Biol. 14, 6107–6116 (1994).PubMedCrossRefGoogle Scholar
  12. 12.
    R. M. Mukey, S. Endo, A. Shenolikar, and R. C. Malenka, Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression, Nature 369, 486–488 (1994).CrossRefGoogle Scholar
  13. 13.
    M. Nibuya, S. Morinobu, and R. S. Duman, Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments, J. Neurosci. 15, 7539–7547 (1995).PubMedGoogle Scholar
  14. 14.
    N. Ozaki, and D. M. Chuang, Lithium increases transcription factor binding to AP-1 and cyclic AMP-responsive element in cultured neurons and rat brain, J. Neurochem. 69, 2336–2344 (1997).PubMedCrossRefGoogle Scholar
  15. 15.
    P. B. Shieh, S. C. Hu, K. Bobb, T. Timmusl, and A. Ghosh, Identification of a signaling pathway involved in calcium regulation of BDNF expression, Neuron 20, 727–740 (1998).PubMedCrossRefGoogle Scholar
  16. 16.
    X. Tao, S. Finkbeiner, D. B. Arnold, A. J. Shaywitz, and M. E. Greenberg, Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism, Neuron 20, 709–726 (1998).PubMedCrossRefGoogle Scholar
  17. 17.
    D. M. Virshup, Protein phosphatase 2A: a panoply of enzymes, Curr. Opin. Cell Biol. 12, 180–185 (2000).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Shigeru Morinobu
    • 1
  • Shigeto Yamawaki
    • 1
  • Takuji Fukumoto
    • 1
  • Seiichi Tsuji
    • 1
  • Takami Suenaga
  • Jun Takahashi
    • 2
  • Kazuhide Tanaka
    • 2
  • Koichiro Fujimaki
    • 2
  1. 1.Hiroshima UniversityHiroshimaJapan
  2. 2.Shiga University Medical ScienceOtsuJapan

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