Role of MKP-1 (DUSP1) in clozapine-induced effects on the ERK1/2 signaling pathway in the rat frontal cortex
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ORIGINAL INVESTIGATION
Role of MKP-1 (DUSP1) in clozapine-induced effects on the ERK1/2 signaling pathway in the rat frontal cortex Se Hyun Kim & Hyun Sook Yu & Hong Geun Park & Soyoung Park & Myoung Suk Seo & Won Je Jeon & Yong Min Ahn & Kyooseob Ha & Soon Young Shin & Yong Sik Kim
Received: 30 December 2012 / Accepted: 30 May 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Rationale Clozapine affects the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in the brain, which plays an important role in its antipsychotic action. However, previous findings are inconsistent, and related molecular mechanisms require further clarification. Objectives Time- and dose-dependent effects of clozapine on the ERK1/2 pathway and its regulatory mechanism were investigated in rat frontal cortex. Methods and results At 15, 30, 60, and 120 min after intraperitoneal injection of clozapine (5, 10, and 20 mg/kg), changes in ERK1/2, its upstream canonical kinases (Raf1 and mitogenactivated protein kinase kinase 1/2 [MEK1/2]), and its downstream molecule (p90 ribosomal S6 kinase [p90RSK]) were
investigated in rat frontal cortex. At 15 min, p-Raf1, pMEK1/2, p-ERK1/2, and p-p90RSK all increased dosedependently. At 30 min, p-ERK1/2 and p-p90RSK showed no significant changes, while dose-dependent increases in p-Raf1 and p-MEK1/2 were found. At 60 and 120 min, although pERK1/2 and p-p90RSK decreased, increases in p-Raf1 and pMEK1/2 were maintained. A clozapine-induced reduction in ERK1/2 phosphorylation was evident at both tyrosine and threonine residues, suggesting the involvement of dual specificity phosphatases (DUSPs; mitogen-activated protein kinase phosphatases [MKPs]). mRNA expression of seven Dusps that can dephosphorylate ERK1/2 were examined; Mkp-1 (Dusp1) mRNA increased following clozapine treatment. Moreover, MKP-1 protein and phosphatase activity increased, and
Soon Young Shin and Yong Sik Kim equally contributed to this study as corresponding authors. S. H. Kim : Y. M. Ahn Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea
S. Y. Shin SMART Institute of Advanced Biomedical Science, Konkuk University Medical Center, Seoul, Republic of Korea
S. H. Kim : H. S. Yu : H. G. Park : S. Park Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea H. S. Yu : H. G. Park Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea M. S. Seo : W. J. Jeon Rebecca L. Cooper Research Laboratories, Mental Health Research Institute, Parkville, VIC, Australia Y. M. Ahn : K. Ha Department of Psychiatry and Behavioral Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea K. Ha Mood Disorders Clinic and Affective Neuroscience Laboratory, Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea
S. Y. Shin (*) Department of Biological Sciences, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-
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