Valproate causes inositol depletion in yeast by decreasing levels of phosphatidic acid and increasing Opi1-mediated repression of INO1 expression.

Valproic acid (VPA) is a widely prescribed mood stabilizer used in the pharmacological management of bipolar disorder (BD), a psychiatric illness that affects 2% of the world's population. Although VPA has been in use for four decades, the therapeutic mechanism of action has not been determined. Inositol depletion is a proposed mechanism, but how VPA depletes inositol is not understood. Using the yeast model, in which the inositol biosynthetic pathway has been well characterized, we show that VPA supplementation leads to decreased levels of phosphatidic acid (PA), including decreased PA species 34:1. Supplementation with PA 34:1 or increasing PA levels by deletion of PAH1 partially rescued VPA-induced repression of INO1. VPA-mediated repression is mediated by the Opi1-Ino2 interaction, as INO1 expression is not repressed in an Ino2 mutant that does not bind to Opi1. The central role of PA in VPA-mediated repression has implications for the mechanism of action of VPA in mammalian cells.