title: Role of MKP-1 (DUSP1) in clozapine-induced effects on the ERK1/2 signaling pathway in the rat frontal cortex.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  Time- and dose-dependent effects of clozapine on the ERK1/2 pathway and its regulatory mechanism were investigated in rat frontal cortex.
  
  
  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 mitogen-activated 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, p-MEK1/2, p-ERK1/2, and p-p90RSK all increased dose-dependently. 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 p-ERK1/2 and p-p90RSK decreased, increases in p-Raf1 and p-MEK1/2 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 binding of MKP-1 to ERK1/2 was also upregulated by clozapine administration.
  
  
  CONCLUSIONS
  In rat frontal cortex, clozapine regulates ERK1/2 phosphorylation via MKP-1, which induces uncoupling between Raf1-MEK1/2 and ERK1/2-p90RSK activity. These findings suggest an important role of MKP-1 in the mechanism of action of clozapine.
authors.affiliation: Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea.
authors.forename: Se Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Yu
authors.forename: Hong Geun
authors.initials: HG
authors.lastname: Park
authors.forename: Soyoung
authors.initials: S
authors.lastname: Park
authors.forename: Myoung Suk
authors.initials: MS
authors.lastname: Seo
authors.forename: Won Je
authors.initials: WJ
authors.lastname: Jeon
authors.forename: Yong Min
authors.initials: YM
authors.lastname: Ahn
authors.forename: Kyooseob
authors.initials: K
authors.lastname: Ha
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Yong Sik
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D005625:Frontal Lobe / Q000187:drug effects; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D017207:Rats, Sprague-Dawley; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D019908:Proto-Oncogene Proteins c-raf; C546782:Raf1 protein, rat; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D003024:Clozapine