title: Valproate alters dopamine signaling in association with induction of Par-4 protein expression.
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.
authors.affiliation: Division of Molecular and Life Science, Department of Life Science, Biotechnology Research Center, Pohang University of Science and Technology, Pohang, Korea.
authors.forename: Saebom
authors.initials: S
authors.lastname: Lee
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Jeong
authors.forename: Young-Un
authors.initials: YU
authors.lastname: Park
authors.forename: Yongdo
authors.initials: Y
authors.lastname: Kwak
authors.forename: Seol Ae
authors.initials: SA
authors.lastname: Lee
authors.forename: Haeryun
authors.initials: H
authors.lastname: Lee
authors.forename: Hyeon
authors.initials: H
authors.lastname: Son
authors.forename: Sang Ki
authors.initials: SK
authors.lastname: Park
mesh_terms: D000818:Animals; D001483:Base Sequence; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D004298:Dopamine / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D017448:Receptors, Dopamine D2; D044462:Receptors, Proteinase-Activated; C481942:protease-activated receptor 4, mouse; D014635:Valproic Acid; D004298:Dopamine