Epi-inositol regulates expression of the yeast INO1 gene encoding inositol-1-P synthase

Abstract

Myo-inositol exerts behavioral effects in animal models of psychiatric disorders and is effective in clinical trials in psychiatric patients. Interestingly, epi-inositol exerts behavioral effects similar to myo-inositol, even though epi-inositol is not a substrate for synthesis of phosphatidylinositol. We postulated that the behavioral effects of epi-inositol may be due to its effects on gene expression. Yeast INO1 expression was measured in northern blots. INM1 was determined by ␤-galactosidase activity in a strain containing the fusion gene INM1-lacZ integrated into the genome. Epi-inositol affects regulation of expression of the INO1 gene (encoding inositol-1-P synthase), even though it cannot support growth of an inositol auxotroph (suggesting that, as in mammalian cells, it is not incorporated into phosphatidylinositol). Like myo-inositol, although to a lesser extent, epi-inositol causes a significant reduction in INO1 expression, and reverses the lithium-or valproate-induced increase in INO1 expression. However, it does not affect regulation of INM1 (encoding inositol monophosphatase), the expression of which is up-regulated by myo-inositol. The observed regulatory effects of epi-inositol on expression of the most highly regulated gene in the inositol biosynthetic pathway may help to explain how this inositol isomer can exert behavioral effects without being incorporated into phosphatidylinositol.

Glycogen Synthase Kinase-3β Haploinsufficiency Mimics the Behavioral and Molecular Effects of Lithium

“…However, several other reports, using similar cell types, found no effect of myo-inositol on lithium-induced changes in growth cone area (Lucas and Salinas, 1997;Lucas et al, 1998;Hall et al, 2000). The reasons for these differences are not clear, but it should be noted that exogenous inositol can have indirect effects not obviously related to depletion of myo-inositol (Hedgepeth et al, 1997;Shaldubina et al, 2002).…”

Stereoselective Synthesis of myo‐, neo‐, L‐chiro, D‐chiro, allo‐, scyllo‐, and epi‐Inositol Systems via Conduritols Prepared from p‐Benzoquinone

“…[17] epi-Inositol 7: Shaldubina and co-workers showed that epi-inositol, another ''non-natural'' isomer, has the ability to modify the expression of the yeast INO1 gene encoding the myo-inositol-3-phosphate synthase. [18] epi-Inositol is thus biologically active in its ability to affect the regulation of the myo-inositol biosynthetic pathway. myo-Inositol phosphates, especially myo-inositol 1,4,5-trisphosphate [myo-Ins(1,4,5)P 3 ], act as intracellular second messengers.…”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…[182] Lithium is a classical inhibitor of the phosphoinositide In yeast epi-inositol has no effect on inositol monophosphatase but does inhibit the expression of the INO1 gene (encoding inositol-1-phosphate synthase) resulting in lower conversion of glucose-6-phosphate to D-myo-inositol 3-phosphate than might otherwise be the case. [184] epi-Inositol thus reverses the lithium-induced increase in INO1 expression. The daily intraperitoneal injection of epi-inositol into rats reduced anxiety levels compared to controls and was more effective than myo-inositol.…”