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Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jan 2;56:168-73. doi: 10.1016/j.pnpbp.2014.09.002. Epub 2014 Sep 20.

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

Author information

1
Dongguk University Research Institute of Biotechnology, 27-3, Phildong 3, Joong-gu, Seoul, 100-715.
2
Department of Child Psychiatry, National Center for Child and Adolescent Psychiatry, Seoul National Hospital, Seoul, 143-711.
3
Department of Neuropsychiatry, Dongguk University Medical School, Dongguk University International Hospital, Goyang-si, Gyeonggi-do, 410-773; Institute of Clinical Psychopharmacology, Dongguk University International Hospital, Goyang-si, Gyeonggi-do, 410-773.
4
Department of Neuropsychiatry, Dongguk University Medical School, Dongguk University International Hospital, Goyang-si, Gyeonggi-do, 410-773; Institute of Clinical Psychopharmacology, Dongguk University International Hospital, Goyang-si, Gyeonggi-do, 410-773. Electronic address: kys@snu.ac.kr.

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.

KEYWORDS:

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

PMID:
25246152
DOI:
10.1016/j.pnpbp.2014.09.002
[Indexed for MEDLINE]

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