Valproate, a mood stabilizer, induces WFS1 expression and modulates its interaction with ER stress protein GRP94.
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.


RESULTS
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.
Kakiuchi
Chihiro
C
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Ishigaki
Shinsuke
S
Oslowski
Christine M
CM
Fonseca
Sonya G
SG
Kato
Tadafumi
T
Urano
Fumihiko
F
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001714:Bipolar Disorder / Q000188:drug therapy; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D013312:Stress, Physiological; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D018692:Antimanic Agents; D015415:Biomarkers; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C053387:endoplasmin; C114987:wolframin protein; D014635:Valproic Acid; D008094:Lithium