Valproate alters dopamine signaling in association with induction of Par-4 protein expression

Saebom Lee; Jaehoon Jeong; Young-Un Park; Yongdo Kwak; Seol Ae Lee; Haeryun Lee; Hyeon Son; Sang Ki Park

doi:10.1371/journal.pone.0045618

Valproate alters dopamine signaling in association with induction of Par-4 protein expression

PLoS One. 2012;7(9):e45618. doi: 10.1371/journal.pone.0045618. Epub 2012 Sep 24.

Authors

Saebom Lee¹, Jaehoon Jeong, Young-Un Park, Yongdo Kwak, Seol Ae Lee, Haeryun Lee, Hyeon Son, Sang Ki Park

Affiliation

¹ Division of Molecular and Life Science, Department of Life Science, Biotechnology Research Center, Pohang University of Science and Technology, Pohang, Korea.

Abstract

Chromatin remodeling through histone modifications has emerged as a key mechanism in the pathophysiology of psychiatric disorders. Valproate (VPA), a first-line medication for bipolar disorder, is known to have histone deacetylase (HDAC) inhibitor activity, but the relationship between its efficacy as a mood stabilizer and HDAC inhibitory activity is unclear. Here we provide evidence that prostate apoptosis response-4 (Par-4), an intracellular binding partner of dopamine D2 receptors (DRD2), plays a role in mediating the effectiveness of VPA. We found that chronic VPA treatment enhanced the expression of Par-4 in cultured neurons and adult mouse brains. This Par-4 induction phenomenon occurred at the transcriptional level and was correlated with an increase in histone H3 and H4 acetylation of the Par-4 promoter regions. Furthermore, chronic VPA treatment potentiated the suppression of the cAMP signaling cascade upon dopamine stimulation, which was blocked by sulpiride treatment. These results indicate that VPA potentiates DRD2 activity by enhancing Par-4 expression via a chromatin remodeling mechanism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Chromatin Assembly and Disassembly / drug effects
Chromatin Immunoprecipitation
DNA Primers
Dopamine / metabolism*
Hippocampus / drug effects
Hippocampus / metabolism
Immunoenzyme Techniques
Mice
Mice, Inbred C57BL
Promoter Regions, Genetic
Real-Time Polymerase Chain Reaction
Receptors, Dopamine D2 / metabolism
Receptors, Proteinase-Activated / biosynthesis*
Receptors, Proteinase-Activated / genetics
Receptors, Proteinase-Activated / metabolism
Signal Transduction / drug effects*
Valproic Acid / pharmacology*

Substances

DNA Primers
Receptors, Dopamine D2
Receptors, Proteinase-Activated
protease-activated receptor 4, mouse
Valproic Acid
Dopamine

Grants and funding

This work was supported by Brain Research Center of the 21st Century Frontier Research Program Grant 2012K001115, and in part by the grants 2012R1A2A2A01012923 and 20090076351 funded by the Ministry of Education, Science and Technology, Republic of Korea.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.