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Perturbation of the Vacuolar ATPase: A NOVEL CONSEQUENCE OF INOSITOL DEPLETION.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2015 Nov 13; Vol. 290 (46), pp. 27460-72. Date of Electronic Publication: 2015 Aug 31. - Publication Year :
- 2015
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Abstract
- Depletion of inositol has profound effects on cell function and has been implicated in the therapeutic effects of drugs used to treat epilepsy and bipolar disorder. We have previously shown that the anticonvulsant 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 vacuolar ATPase (V-ATPase). Inositol depletion caused by starvation of ino1Δ cells perturbed the vacuolar structure and decreased V-ATPase activity and proton pumping in isolated vacuolar vesicles. VPA compromised the dynamics of phosphatidylinositol 3,5-bisphosphate (PI3,5P2) and greatly reduced V-ATPase proton transport in inositol-deprived wild-type cells. Osmotic stress, known to increase PI3,5P2 levels, did not restore PI3,5P2 homeostasis nor did it induce vacuolar fragmentation in VPA-treated cells, suggesting that perturbation of the V-ATPase is a consequence of altered PI3,5P2 homeostasis under inositol-limiting conditions. This study is 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.<br /> (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Drug Resistance, Fungal genetics
Gene Deletion
Homeostasis
Inositol genetics
Myo-Inositol-1-Phosphate Synthase genetics
Osmotic Pressure
Phosphatidylinositol Phosphates metabolism
Protein Transport
Saccharomyces cerevisiae drug effects
Saccharomyces cerevisiae enzymology
Saccharomyces cerevisiae genetics
Saccharomyces cerevisiae Proteins genetics
Vacuolar Proton-Translocating ATPases genetics
Anticonvulsants pharmacology
Inositol deficiency
Intramolecular Lyases antagonists & inhibitors
Vacuolar Proton-Translocating ATPases metabolism
Vacuoles enzymology
Valproic Acid pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 290
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26324718
- Full Text :
- https://doi.org/10.1074/jbc.M115.683706