Molecular Mechanisms Regulating The Response Of Budding Yeast To Lithium Stress

Lithium was used to treat bipolar disorder over50years ago and is stillcommonly used to treat its manic phase. However, how these pharmacological actionsof lithium produce these clinical effects is not completely clear。Understanding themechanisms by which lithium regulates cellular processes would help us to explainthe molecular basis for the beneficial and toxic effects of lithium. Collections of yeastgene deletions have been successfully used in the characterization of gene-drug andpathway-drug interactions in recent years. To have a global view of lithium effects oneukaryotic cells, we have identified114lithium-sensitive and6lithium-tolerant genemutations from a genome-scale genetic screen in Saccharomyces cerevisiae in thisstudy.Some of these identified lithium-sensitive mutations are of genes previouslyreported to be involved in potassium transport, whereas some of them are of genesinvolved in the vacuolar protein sorting (VPS) pathway, mainly functioning in themembrane docking and fusion. These results indicate that many targets of lithiumexist in yeast cells. Accordingly, the lithium-sensitive phenotypes for one third ofidentified vps mutants well correlate to their intracellular lithium contents in responseto lithium stress. This indicates the integrity of the VPS pathway is critic for the ionhomeostasis in yeast cells.The halotolerant protein kinase Hal5p, a regulator of the potassium transporterTrk1p, is shown to be the high-copy suppressor of nearly one third of identifiedlithium-sensitive mutations of genes involved in the VPS pathway as well as in thebiosynthesis of ergosterol. These results suggest that Hal5p-mediated ion homeostasisis important for these two biological processes.Six lithium-tolerant mutants identified from the genomescale screen accumulatedsimilar or less intracellular lithium contents in response to lithium stress. Over-expression of HAL5further increased the lithium tolerance of the nrg1/mutant, butnot other5mutants. We also found that HAL5expression is higher in ure2/mutantthan the wild type and is induced in response to calcium stress.