Valproate independently activates Snf1, inhibits TORC1, and induces repression of INO1 transcription by increasing nuclear localization of Opi1.

Valproate (VPA), a drug used to treat neurological disorders such as epilepsy, bipolar disorder, and migraines, induces inositol depletion in the brain by preventing its synthesis, which is a hypothesized therapeutic mechanism for mood stabilizing drugs. However, the mechanism by which this occurs is not known. VPA treatment reduces activity of the enzyme that catalyzes the rate-limiting step of inositol synthesis, myo-inositol-3-phosphate synthase (MIPS). Utilizing the yeast model, we report that VPA induces repression of the MIPS-encoding gene INO1 by increasing nuclear translocation of the transcriptional repressor Opi1. In addition, VPA rapidly inhibits TORC1, an activator of INO1 expression, and increased TORC1 activity partially rescues expression of INO1. VPA also rapidly activates Snf1, a known regulator of INO1. However, neither TORC1 inhibition nor Snf1 activation is required for repression of INO1 by VPA. We postulate that it is likely that the pleiotropic effects of VPA not only bring about the initial decrease in MIPS protein levels by repressing INO1 transcription but also by preventing recovery of inositol synthesis by downregulating MIPS translation. These independent effects of VPA underlie the complex mechanisms that collectively induce inositol depletion.