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

FEBS Lett. 2004 Feb 27;560(1-3):115-9. doi: 10.1016/S0014-5793(04)00082-1.

Abstract

We investigated the effect of 10 microM clozapine on the activity of glycogen synthase kinase-3beta (GSK-3beta) and its upstream and downstream molecules in SH-SY5Y human neuroblastoma cells. Clozapine activates both Akt- and Dvl-mediated phosphorylation of GSK-3beta through phosphorylation at Ser9, and increased total cellular and intranuclear levels of beta-catenin. Pretreatment with the specific inhibitor of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, LY294002 (20 microM), prevented the phosphorylation of Akt but did not affect the phosphorylation of GSK-3beta. These results suggest that clozapine regulates the phosphorylation of GSK-3beta through Wnt signal pathways involving Dvl upstream but not through the PI3K-Akt pathway in SH-SY5Y cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / chemistry
  • Chromones / pharmacology
  • Clozapine / pharmacology*
  • Culture Media, Serum-Free
  • Cytoskeletal Proteins / analysis
  • Cytoskeletal Proteins / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3 / chemistry
  • Glycogen Synthase Kinase 3 / drug effects
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Morpholines / pharmacology
  • Neuroblastoma / enzymology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Serine / metabolism
  • Signal Transduction*
  • Time Factors
  • Trans-Activators / analysis
  • Trans-Activators / drug effects
  • Wnt Proteins
  • Zebrafish Proteins*
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Chromones
  • Culture Media, Serum-Free
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Morpholines
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Serine
  • AKT1 protein, human
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Clozapine