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

Songhee Jeon1, Yeni Kim2, In-Won Chung3

  • 1Dongguk University Research Institute of Biotechnology, 27-3, Phildong 3, Joong-gu, Seoul, 100-715.

Progress in Neuro-Psychopharmacology & Biological Psychiatry
|September 24, 2014
PubMed
Abstract

Insights

Clozapine increases chloride channel 4 (CLC-4) expression in brain cells, mediated by CREB activation. This clozapine-induced CLC-4 may influence cyclin-dependent kinase 5 (CDK5) expression, potentially contributing to its therapeutic effects.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Second-generation antipsychotics, like clozapine, may promote neurite outgrowth.
  • Chloride channel 4 (CLC-4) is crucial for nerve growth factor-induced neurite outgrowth in neuronal cells.

Purpose of the Study:

  • To investigate if clozapine induces CLC-4 expression in neuroblastoma and glioma cells.
  • To elucidate the signaling pathway involved in clozapine-induced CLC-4 expression.
  • To identify molecular targets of clozapine-induced CLC-4.

Main Methods:

  • Examined clozapine's effect on CLC-4 expression in SH-SY5Y and U87 cells.
  • Assessed cAMP response element-binding protein (CREB) phosphorylation to understand the signaling pathway.
  • Utilized CLC-4 siRNA for functional knockdown to identify downstream targets.

Main Results:

  • Clozapine significantly increased CLC-4 expression in both cell lines.
  • Clozapine induced CREB phosphorylation, which was suppressed by a protein kinase A inhibitor.
  • Knockdown of CLC-4 reduced clozapine-induced cyclin-dependent kinase 5 (CDK5) expression.

Conclusions:

  • Clozapine's therapeutic effects may involve CLC-4 induction, dependent on CREB activation via PKA.
  • CLC-4 knockdown's impact on CDK5 expression suggests CDK5 is a potential molecular target of clozapine.
Keywords:
Chloride channel-4ClozapineCyclin-dependent kinase 5SH-SY5YU87

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