UMMS Affiliation

Program in Gene Function and Expression; Program in Molecular Medicine

Publication Date


Document Type



Animals; Antimanic Agents; Biological Markers; Bipolar Disorder; Cell Line; Endoplasmic Reticulum; Gene Expression Regulation; Humans; Lithium; Membrane Glycoproteins; Membrane Proteins; Mice; Promoter Regions, Genetic; Stress, Physiological; Valproic Acid


Biochemistry, Biophysics, and Structural Biology | Genetics and Genomics | Life Sciences | Medicine and Health Sciences


BACKGROUND: Valproate 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 FINDINGS: Here 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.

CONCLUSIONS: These results suggest that the therapeutic effects of valproate in bipolar disorder may be mediated by WFS1 expression and its dissociation from GRP94.

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Copyright: © 2009 Kakiuchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI of Published Version



Kakiuchi C, Ishigaki S, Oslowski CM, Fonseca SG, Kato T, et al. (2009) Valproate, a Mood Stabilizer, Induces WFS1 Expression and Modulates Its Interaction with ER Stress Protein GRP94. PLoS ONE 4(1): e4134. doi:10.1371/journal.pone.0004134. Link to article on publisher's site

Journal/Book/Conference Title

PloS one

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