VPA inhibits myo‐inositol phosphate synthase activity by inhibition of Gsk3

Abstract

Valproic acid (VPA) has been used for decades for the treatment of bipolar disorder. Yet, the therapeutic mechanism of VPA is not understood, hindering the development of more effective drugs. VPA causes inositol depletion in the human brain and in yeast cells. A similar degree of inositol depletion was observed in the yeast gsk3Δ mutant, in which the four glycogen synthase kinase 3 (GSK3) homologs were deleted. VPA was shown to inhibit Gsk3 in mammalian cells. These findings suggest that Gsk3 may play a role in inositol metabolism, and that VPA may cause inositol depletion by inhibiting Gsk3. The rate limiting enzyme in yeast inositol de novo synthesis is myo‐inositol phosphate synthase (MIPS). We hypothesize that Gsk3 is required for optimal MIPS activity. Consistent with this, the gsk3Δ mutant exhibited decreased MIPS activity. Although VPA inhibited MIPS activity in wild type cells, it did not inhibit MIPS in gsk3Δ cells, suggesting that VPA‐induced inositol depletion occurs by inhibition of Gsk3, leading to decreased MIPS activity. Of the four GSK3 homologs, we show that MCK1 is required for optimal inositol synthesis. mck1Δ exhibited multiple features of inositol depletion, including inositol‐dependent growth and decreased intracellular inositol. We conclude that inhibition of MIPS by VPA is dependent on Gsk3.Funding: NIH‐DK081367 & Enhancement Award for Doctoral Student Travel