Originally published as Genetics Published Articles Ahead of Print on February 7, 2007.

Genetics, Vol. 175, 1695-1705, April 2007, Copyright © 2007
doi:10.1534/genetics.107.070946

Valproic Acid Affects Membrane Trafficking and Cell-Wall Integrity in Fission Yeast

Makoto Miyatake^*, Takayoshi Kuno^*, Ayako Kita, Kosaku Katsura, Kaoru Takegawa, Satoshi Uno^*, Toshiya Nabata^* and Reiko Sugiura^,1

^* Division of Molecular Pharmacology and Pharmacogenomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan, Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka 577-8502, Japan and Department of Life Sciences, Faculty of Agriculture, Kagawa University, Kagawa 761-0795, Japan

¹ Corresponding author: Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University, Kowakae 3-4-1, Higashi-Osaka, Osaka, 577-8502, Japan.
E-mail: sugiurar{at}phar.kindai.ac.jp

Valproic acid (VPA) is widely used to treat epilepsy and manic-depressive illness. Although VPA has been reported to exert a variety of biochemical effects, the exact mechanisms underlying its therapeutic effects remain elusive. To gain further insights into the molecular mechanisms of VPA action, a genetic screen for fission yeast mutants that show hypersensitivity to VPA was performed. One of the genes that we identified was vps45⁺, which encodes a member of the Sec1/Munc18 family that is implicated in membrane trafficking. Notably, several mutations affecting membrane trafficking also resulted in hypersensitivity to VPA. These include ypt3⁺ and ryh1⁺, both encoding a Rab family protein, and apm1⁺, encoding the µ1 subunit of the adaptor protein complex AP-1. More importantly, VPA caused vacuolar fragmentation and inhibited the glycosylation and the secretion of acid phosphatase in wild-type cells, suggesting that VPA affects membrane trafficking. Interestingly, the cell-wall-damaging agents such as micafungin or the inhibition of calcineurin dramatically enhanced the sensitivity of wild-type cells to VPA. Consistently, VPA treatment of wild-type cells enhanced their sensitivity to the cell-wall-digesting enzymes. Altogether, our results suggest that VPA affects membrane trafficking, which leads to the enhanced sensitivity to cell-wall damage in fission yeast.

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