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Inositol Depletion Perturbs the Vacuolar‐ATPase: A Novel Mechanism of Action of Valproate
Author(s) -
Deranieh Rania,
Shi Yihui,
Tarsio Mauraeen,
Kane Patricia,
Greenberg Miriam
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.715.50
Subject(s) - inositol , mutant , inositol phosphate , chemistry , v atpase , biochemistry , atpase , microbiology and biotechnology , enzyme , biology , receptor , gene
Depletion of inositol has profound effects on cell function and has been implicated in the therapeutic effects of drugs used to treat bipolar disorder. We have previously shown that one such drug, valproate (VPA), depletes inositol by inhibiting myo ‐inositol 3‐phosphate synthase, the enzyme that catalyzes the first and rate‐limiting step of inositol biosynthesis. To elucidate the cellular consequences of inositol depletion, we screened the yeast deletion collection for VPA‐sensitive mutants and identified mutants in vacuolar sorting and the V‐ATPase. Inositol depletion caused by VPA or by starvation of ino1Δ cells perturbed the vacuolar structure, decreased V‐ATPase activity and proton pumping in isolated vacuolar vesicles. VPA compromised the levels of PI3,5P 2 , which is necessary for stabilization of the V‐ATPase complex, and resulted in reduced V‐ATPase activity. Osmotic stress, known to increase PI3,5P 2 levels, did not restore the compromised PI3,5P 2 levels, nor did it induce vacuolar fragmentation in VPA‐treated cells, suggesting that perturbation of the V‐ATPase is a consequence of altered PI3,5P 2 homeostasis under inositol‐limiting conditions. The findings of this study are the first to demonstrate that inositol depletion caused by starvation of an inositol synthesis mutant or by the inositol‐depleting drug VPA leads to perturbation of the V‐ATPase.