Perturbation of the Vacuolar ATPase: A NOVEL CONSEQUENCE OF INOSITOL DEPLETION.

The Journal of Biological Chemistry
Rania M DeraniehMiriam L Greenberg

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 ...Continue Reading

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Citations

Mar 10, 2016·Molecular and Cellular Biology·Anna D FrejRobin S B Williams
Oct 27, 2016·Scientific Reports·Kristelle Desfossés-BaronHugo Wurtele
May 1, 2016·Future Neurology·Wenxi Yu, Miriam L Greenberg
Oct 25, 2017·Frontiers in Microbiology·Julien ChaillotAdnane Sellam
Aug 27, 2018·Histochemistry and Cell Biology·Nikhil R YedullaBhanu P Jena
Jul 1, 2017·Functional Plant Biology : FPB·Vadim Pérez Koldenkova, Noriyuki Hatsugai
Oct 29, 2020·G3 : Genes - Genomes - Genetics·Michael C AyersJennifer E G Gallagher
Feb 11, 2020·Poultry Science·Fernando Gonzalez-UarquinKorinna Huber

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