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The effects of clozapine on the GSK-3-mediated signaling pathway

Ung Gu Kang1, Myoung Suk Seo, Myoung-Sun Roh

  • 1Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-799, South Korea.

FEBS Letters
|February 28, 2004
PubMed

Insights

Clozapine impacts glycogen synthase kinase-3beta (GSK-3beta) activity in neuroblastoma cells. It activates GSK-3beta via the Dvl-Wnt pathway, not the PI3K-Akt pathway, influencing beta-catenin levels.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Glycogen synthase kinase-3beta (GSK-3beta) is a key regulator in cellular signaling pathways.
  • Dysregulation of GSK-3beta is implicated in various neurological disorders.
  • Understanding drug effects on GSK-3beta is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the effect of clozapine on GSK-3beta activity and associated signaling pathways.
  • To determine whether clozapine's effects are mediated through the PI3K-Akt or Wnt pathways.
  • To examine clozapine's impact on beta-catenin levels in SH-SY5Y neuroblastoma cells.

Main Methods:

  • Utilized SH-SY5Y human neuroblastoma cells.
  • Administered clozapine (10 microM) and LY294002 (20 microM, a PI3K-Akt inhibitor).
  • Assessed phosphorylation of GSK-3beta (at Ser9), Akt, and levels of beta-catenin.

Main Results:

  • Clozapine activated GSK-3beta phosphorylation at Ser9, indicating inactivation.
  • This activation was linked to both Akt- and Dvl-mediated pathways.
  • Clozapine increased total and intranuclear beta-catenin levels.
  • LY294002 inhibited Akt phosphorylation but did not affect GSK-3beta phosphorylation.

Conclusions:

  • Clozapine regulates GSK-3beta phosphorylation primarily through Wnt pathway components involving Dvl.
  • The PI3K-Akt pathway is not the primary mediator of clozapine's effect on GSK-3beta in these cells.
  • Clozapine modulates beta-catenin signaling, suggesting potential roles in neuroprotection or neurodegeneration.

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