Valproate, a Mood Stabilizer, Induces WFS1 Expression and Modulates Its Interaction with ER Stress Protein GRP94

Chihiro Kakiuchi,Sonya G Fonseca,Fumihiko Urano,Shinsuke Ishigaki,Tadafumi Kato,Christine M Oslowski,Thomas Preiss

doi:10.1371/journal.pone.0004134

Abstract

BackgroundValproate is a standard treatment for bipolar disorder and a first-line mood stabilizer. The molecular mechanisms underlying its actions in bipolar disorder are unclear. It has been suggested that the action of valproate is linked to changes in gene expression and induction of endoplasmic reticulum (ER) stress-response proteins.Principal FindingsHere we show that valproate modulates the ER stress response through the regulation of WFS1, an important component for mitigating ER stress. Therapeutic concentrations of valproate induce expression of WFS1 mRNA and activate the WFS1 promoter. In addition, WFS1 forms a complex with GRP94, an ER stress-response protein, in which valproate dose-dependently enhances its dissociation from GRP94.ConclusionsThese results suggest that the therapeutic effects of valproate in bipolar disorder may be mediated by WFS1 expression and its dissociation from GRP94.

Highlights

Bipolar disorder is a severe mental disorder characterized by recurrent episodes of mania and depression, affecting about 0.5– 1% of the population [1]
These results suggest that the therapeutic effects of valproate in bipolar disorder may be mediated by WFS1 expression and its dissociation from GRP94
These findings suggest that the modulation of endoplasmic reticulum (ER) stress by WFS1 and GRP94 may be involved in bipolar disorder

Summary

Introduction

Bipolar disorder is a severe mental disorder characterized by recurrent episodes of mania and depression, affecting about 0.5– 1% of the population [1]. Valproate increases the DNA binding of activator protein 1 (AP-1), a transcription factor which is a heterodimeric protein composed of proteins belonging to the cFos, c-Jun, and ATF families [6,7] This may lead to enhanced expression of AP-1 target genes that have important functions in neurons. Valproate has been characterized as a histone deacetylases (HDAC) inhibitor and can regulate gene expression through epigenetic mechanisms [8]. These findings suggest an attractive possibility that valproate increases expression of multiple genes that have protective effects against bipolar disorder. It has been suggested that the action of valproate is linked to changes in gene expression and induction of endoplasmic reticulum (ER) stress-response proteins

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Conclusion