Valproate activates the Snf1 kinase in Saccharomyces cerevisiae by decreasing the cytosolic pH |
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Authors: | Michael Salsaa,Kerestin Aziz,Pablo Lazcano,Michael W. Schmidtke,Maureen Tarsio,Maik Hü ttemann,Christian A. Reynolds,Patricia M. Kane,Miriam L. Greenberg |
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Affiliation: | 1.Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA;2.Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA;3.Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, Michigan, USA;4.Department of Emergency Medicine, School of Medicine, Wayne State University, Detroit, Michigan, USA;5.Department of Biotechnology, University of Rijeka, Rijeka, Croatia |
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Abstract: | Valproate (VPA) is a widely used mood stabilizer, but its therapeutic mechanism of action is not understood. This knowledge gap hinders the development of more effective drugs with fewer side effects. Using the yeast model to elucidate the effects of VPA on cellular metabolism, we determined that the drug upregulated expression of genes normally repressed during logarithmic growth on glucose medium and increased levels of activated (phosphorylated) Snf1 kinase, the major metabolic regulator of these genes. VPA also decreased the cytosolic pH (pHc) and reduced glycolytic production of 2/3-phosphoglycerate. ATP levels and mitochondrial membrane potential were increased, and glucose-mediated extracellular acidification decreased in the presence of the drug, as indicated by a smaller glucose-induced shift in pH, suggesting that the major P-type proton pump Pma1 was inhibited. Interestingly, decreasing the pHc by omeprazole-mediated inhibition of Pma1 led to Snf1 activation. We propose a model whereby VPA lowers the pHc causing a decrease in glycolytic flux. In response, Pma1 is inhibited and Snf1 is activated, resulting in increased expression of normally repressed metabolic genes. These findings suggest a central role for pHc in regulating the metabolic program of yeast cells. |
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Keywords: | bipolar disorder cytosolic pH inositol 1 4 5-triphosphate glycolysis mitochondrial membrane potential Pma1 H+-ATPase SNF1/AMPK valproate weak acid preservatives |
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