Myo-inositol-1-phosphate (MIP) synthase: a possible new target for antibipolar drugs.

Inositol metabolism is well characterized in yeast at a molecular level, and yeast is the only eukaryote in which genetic, molecular and functional genomic approaches to identify lithium. valproate and inositol targets may be combined readily. It has been shown that lithium inhibits yeast inositol monophosphatase (encoded by INM1 and INM2), and both valproate and lithium reduce intracellular inositol. Unlike lithium, valproate causes a decrease in intracellular inositol-1-phosphate as well. suggesting that myo-inositol-1-P (MIP) synthase is a site of valproate action in the yeast PI cycle. MIP synthase is the rate-limiting step in inositol biosynthesis and is highly regulated in response to inositol. Yeast genes that are affected by both lithium and valproate in the phosphoinositide pathways (INO1 increased over 10-fold, INO2 increased twofold and INM1 decreased about twofold) have been identified. It has also been reported previously that both lithium and inositol mildly up-regulate IMPA1 (encoding mammalian inositol monophosphatase) expression in human cells. These findings indicate that IMPA is regulated only mildly by lithium, and therefore may not be the major target in the inositol pathway. Given the substantial evidence for the role of inositol in the mechanism of action of lithium and valproate. the opposing and mild effects of lithium on the genes encoding inositol monophosphatase in yeast and human cells, but the powerful effect of lithium and valproate on INO1 in yeast, it is hypothesized that human hIANO1 is a factor in the psychopharmacology of mood stabilizers.