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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)425-437
Number of pages13
JournalPsychopharmacology
Volume230
Issue number3
DOIs
StatePublished - 1 Dec 2013

Fingerprint

Mitogen-Activated Protein Kinase Phosphatases
Dual Specificity Phosphatase 1
Mitogen-Activated Protein Kinase 3
Clozapine
Mitogen-Activated Protein Kinase 1
Frontal Lobe
90-kDa Ribosomal Protein S6 Kinases
MAP Kinase Kinase 2
MAP Kinase Kinase 1
MAP Kinase Kinase Kinase 1
Dual-Specificity Phosphatases
Phosphorylation
Messenger RNA
Phosphoprotein Phosphatases
Threonine
Intraperitoneal Injections
Antipsychotic Agents
Tyrosine

Keywords

  • Antipsychotics
  • Dual specificity phosphatase
  • Mitogen-activated protein kinase

Cite this

Kim, Se Hyun ; Yu, Hyun Sook ; Park, Hong Geun ; Park, Soyoung ; Seo, Myoung Suk ; Jeon, Won Je ; Ahn, Yong Min ; Ha, Kyooseob ; Shin, Soon Young ; Kim, Yong Sik. / Role of MKP-1 (DUSP1) in clozapine-induced effects on the ERK1/2 signaling pathway in the rat frontal cortex. In: Psychopharmacology. 2013 ; Vol. 230, No. 3. pp. 425-437.
@article{c7aabf1516ef46098960209d4322d0df,
title = "Role of MKP-1 (DUSP1) in clozapine-induced effects on the ERK1/2 signaling pathway in the rat frontal cortex",
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 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.",
keywords = "Antipsychotics, Dual specificity phosphatase, Mitogen-activated protein kinase",
author = "Kim, {Se Hyun} and Yu, {Hyun Sook} and Park, {Hong Geun} and Soyoung Park and Seo, {Myoung Suk} and Jeon, {Won Je} and Ahn, {Yong Min} and Kyooseob Ha and Shin, {Soon Young} and Kim, {Yong Sik}",
year = "2013",
month = "12",
day = "1",
doi = "10.1007/s00213-013-3165-y",
language = "English",
volume = "230",
pages = "425--437",
journal = "Psychopharmacology",
issn = "0033-3158",
publisher = "Springer Verlag",
number = "3",

}

Role of MKP-1 (DUSP1) in clozapine-induced effects on the ERK1/2 signaling pathway in the rat frontal cortex. / Kim, Se Hyun; Yu, Hyun Sook; Park, Hong Geun; Park, Soyoung; Seo, Myoung Suk; Jeon, Won Je; Ahn, Yong Min; Ha, Kyooseob; Shin, Soon Young; Kim, Yong Sik.

In: Psychopharmacology, Vol. 230, No. 3, 01.12.2013, p. 425-437.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of MKP-1 (DUSP1) in clozapine-induced effects on the ERK1/2 signaling pathway in the rat frontal cortex

AU - Kim, Se Hyun

AU - Yu, Hyun Sook

AU - Park, Hong Geun

AU - Park, Soyoung

AU - Seo, Myoung Suk

AU - Jeon, Won Je

AU - Ahn, Yong Min

AU - Ha, Kyooseob

AU - Shin, Soon Young

AU - Kim, Yong Sik

PY - 2013/12/1

Y1 - 2013/12/1

N2 - 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 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.

AB - 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 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.

KW - Antipsychotics

KW - Dual specificity phosphatase

KW - Mitogen-activated protein kinase

UR - http://www.scopus.com/inward/record.url?scp=84888646035&partnerID=8YFLogxK

U2 - 10.1007/s00213-013-3165-y

DO - 10.1007/s00213-013-3165-y

M3 - Article

C2 - 23771439

AN - SCOPUS:84888646035

VL - 230

SP - 425

EP - 437

JO - Psychopharmacology

JF - Psychopharmacology

SN - 0033-3158

IS - 3

ER -