New insights into the molecular targets of lithium and valproate.

摘要

Lithium (Li) and valproate (VPA) are two FDA approved drugs to treat bipolar disorder. Efforts to design more effective treatment for bipolar disorder are hampered by the fact that the therapeutic mechanisms of Li and VPA are not known. This study utilized the yeast model Saccharomyces cerevisiae to gain insight into the molecular targets of these drugs.; A classical genetic screen was used to identify yeast mutants hypersensitive to Li and VPA. This study showed that a loss of function allele of TPI1, which encodes triose phosphate isomerase, led to a 30-fold increase in intracellular DHAP levels. The increased DHAP in tpi1 strongly inhibited activity of the inositol biosynthetic enzyme myo-inositol-3-phosphate synthase and led to inositol auxotrophy. This study is the first to establish a connection between perturbation of glycolysis and inhibition of de novo inositol biosynthesis.; To further identify targets of Li and VPA, a genome-wide screen of 4815 yeast deletion strains was carried out to identify mutants with altered sensitivity to Li and VPA. This screen identified the secretory pathway as a possible target of both drugs, as 17 secretory mutants were hypersensitive to Li and VPA. In addition, 48 deletion mutants that are resistant to Li were identified. These included pho84, 9 mutants in the SAGA transcriptional regulatory complex that are required for PHO84 expression and 10 non-SAGA mutants that exhibited dramatically reduced expression of PHO84. Plasmid based expression of PHO84 or the human gene hOCT2, which shares homology with PHO84 complemented the Li resistance phenotype of the pho84 mutant. These results demonstrated that PHO84 is partly responsible for Li uptake in yeast.; Inositol depletion is an outcome of treatment with both Li and VPA, may thus be a component of the therapeutic mechanism. Therefore, we initiated studies to identify other inositol-depleting compounds similar in structure to VPA. This study found that 4 short straight-chain carboxylic acids (C6:0, C8:0, C9:0, C10:0) and 2 short branched-chain carboxylic acids, ethylhexanoate and methyloctanoate, caused inositol depletion. This study may shed light on potential new antibipolar drugs.