The effects of clozapine on the GSK-3-mediated signaling pathway.
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.
Kang
Ung Gu
UG
Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-799, South Korea.
Seo
Myoung Suk
MS
Roh
Myoung-Sun
MS
Kim
Yeni
Y
Yoon
Se Chang
SC
Kim
Yong Sik
YS
D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry; D002867:Chromones / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000032:analysis / Q000187:drug effects; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D002867:Chromones; D003024:Clozapine; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C000605506:GSK3B protein, human