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Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

Min-Huei Liang1, Jens R Wendland, De-Maw Chuang

  • 1Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, 10 Center Dr. MSC 1363, Bethesda, MD, USA.

Molecular and Cellular Neurosciences
|December 14, 2007
PubMed

Insights

Lithium inhibits Smad-dependent gene transcription in rat brain cells by altering key signaling pathways. This mechanism may offer new therapeutic strategies for mood disorders and neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Smad proteins are crucial for transforming growth factor-beta (TGF-beta) signaling in the central nervous system.
  • TGF-beta and its target gene, plasminogen activator inhibitor type-1 (PAI-1), are linked to neurodegenerative and mood disorders.
  • Glycogen synthase kinase-3beta (GSK-3beta) depletion affects Smad3/4-dependent transcription and PAI-1 expression.

Purpose of the Study:

  • To investigate the mechanism by which lithium, a bipolar disorder treatment, affects Smad-dependent signaling in rat neurons.
  • To elucidate the role of cAMP-protein kinase A (PKA), AKT-GSK-3beta, and CRE-dependent pathways in lithium's action on Smad signaling.

Main Methods:

  • Utilized neuron-enriched cerebral cortical cultures from rats.
  • Examined the effects of lithium on cAMP-PKA, AKT-GSK-3beta, and CRE-dependent signaling pathways.
  • Assessed lithium's impact on Smad3/4-dependent gene transcription, pCREB(Ser133) levels, pCREB(Ser133)-p300/CBP interaction, and Smad3/4-p300/CBP complex formation.

Main Results:

  • Lithium inhibits Smad3/4-dependent gene transcription in rat cortical neurons.
  • Lithium activates cAMP-PKA, AKT-GSK-3beta, and CRE-dependent pathways.
  • Lithium increases pCREB(Ser133) levels and its interaction with p300/CBP, disrupting the Smad3/4-p300/CBP complex and suppressing gene transcription.

Conclusions:

  • Lithium exerts its inhibitory effect on Smad-dependent signaling through modulation of PKA, AKT-GSK-3beta, and CRE pathways.
  • The findings provide insights into the molecular mechanisms underlying lithium's therapeutic effects in mood disorders.
  • This study highlights potential therapeutic targets for neurodegenerative diseases and mood disorders involving Smad signaling.

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