Journal article
N. Yedulla, A. Naik, Keith M. Kokotovich, Wenxi Yu, M. Greenberg, B. Jena
2018
2018
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APA
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Yedulla, N., Naik, A., Kokotovich, K. M., Yu, W., Greenberg, M., & Jena, B. (2018). Valproate Prevents a Cytosolic vH+ATPase Subunit Insertion on Insulin Granule Membrane and Compromises Insulin Release in Min6 Cells.
Chicago/Turabian
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Yedulla, N., A. Naik, Keith M. Kokotovich, Wenxi Yu, M. Greenberg, and B. Jena. “Valproate Prevents a Cytosolic VH+ATPase Subunit Insertion on Insulin Granule Membrane and Compromises Insulin Release in Min6 Cells” (2018).
MLA
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Yedulla, N., et al. Valproate Prevents a Cytosolic VH+ATPase Subunit Insertion on Insulin Granule Membrane and Compromises Insulin Release in Min6 Cells. 2018.
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@article{n2018a,
title = {Valproate Prevents a Cytosolic vH+ATPase Subunit Insertion on Insulin Granule Membrane and Compromises Insulin Release in Min6 Cells},
year = {2018},
author = {Yedulla, N. and Naik, A. and Kokotovich, Keith M. and Yu, Wenxi and Greenberg, M. and Jena, B.}
}
Abstract
The vacuolar proton pump, vH+ATPase transfers protons (H+) across cell membranes which helps maintain pH gradient within cells necessary for various cellular functions. It is a two‐part pump containing a membrane (V0) and a soluble cytosolic (V1) domain with each domain consisting of multiple subunits. In secretory cells, such as neurons, vH+ATPase acidifies synaptic vesicles, which is essential for neurotransmitter uptake, storage and exocytosis. Valproate, an FDA approved, anti‐ epileptic drug has been shown to disturb vH+ATPase function in yeasts, by inhibiting myo‐inositol phosphatase (MIPS), the first and the rate‐limiting enzyme in inositol biosynthesis leading to inositol depletion. Additionally, vH+ATPase is present on the membrane of insulin secreting granules (ISG) within pancreatic β cells. Several studies have suggested vH+ATPase requirement for insulin maturation within ISGs. Further, pancreatic islets containing a mutant vH+ATPase isoform exhibit compromised insulin release function, however, the mechanism is unknown. Here, we demonstrate that clinical dose of valproate (1mM) significantly reduced glucose‐ stimulated insulin secretion in mouse pancreatic insulinoma (Min6) cells. Moreover, valproate caused maximal inositol depletion in Min6 cells after 5 hours of incubation with the drug. Dual immunofluorescence staining of valproate‐treated Min6 cells demonstrates almost no localization of one of the cytosolic subunits of vH+ATPase (subunit C) on ISGs, unlike in control. These results conclude that inositol depletion in Min6 cells caused by valproate precludes insertion of vH+ATPase subunit C on ISG membrane, rendering the ISGs less competent for glucose‐stimulated insulin secretion.