Clozapine induces chloride channel-4 expression through PKA activation and modulates CDK5 expression in SH-SY5Y and U87 cells

Songhee Jeon, Yeni Kim, In Won Chung, Yong Sik Kim

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Objectives: Second-generation antipsychotic drugs, such as clozapine, were reported to enhance neurite outgrowth by nerve growth factor in PC12 cells. The authors previously showed that chloride channel 4 (CLC-4) is responsible for nerve growth factor-induced neurite outgrowth in neuronal cells. In this study, we examined whether clozapine induces CLC-4 in neuroblastoma and glioma cells. Methods: The effect of clozapine on CLC-4 expression was examined in neuroblastoma (SH-SY5Y) and glioma (U87) cells. To investigate the signaling pathway responsible for clozapine-induced CLC-4 expression, the phosphorylation of cAMP response element-binding protein (CREB), which binds CRE in the promoter of the human CLC-4 gene, was examined. To identify the target of clozapine induced CLC-4, CLC-4 siRNA was introduced to neuroblastoma and glioma cells for functional knockdown. Results: We observed that clozapine increased CLC-4 expression in both SH-SY5Y and U87 cells. Clozapine induced CREB phosphorylation, but in the presence of inhibitor of protein kinase A (an upstream kinase of CREB) clozapine-induced CLC-4 expression was suppressed. Finally, we found that CLC-4 knockdown suppressed clozapine-induced cyclin-dependent kinase 5 (CDK5) expression in SH-SY5Y and U-87 cells suggesting CDK5 as potential molecular target of clozapine induced CLC-4 expression. Conclusions: The results of the present study suggest that clozapine's therapeutic effect may include the induction of CLC-4 which is dependent on CREB activation via PKA. We also found that functional knockdown of CLC-4 resulted in reduction of CDK5 expression, which may also be implicated in clozapine's therapeutic effect.

Original languageEnglish
Pages (from-to)168-173
Number of pages6
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume56
DOIs
StatePublished - 2 Jan 2015

Keywords

  • Chloride channel-4
  • Clozapine
  • Cyclin-dependent kinase 5
  • SH-SY5Y
  • U87

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