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Eukaryotic Cell, June 2007, p. 899-906, Vol. 6, No. 6
1535-9778/07/$08.00+0     doi:10.1128/EC.00104-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Attenuation of Phospholipid Signaling Provides a Novel Mechanism for the Action of Valproic Acid ^,

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, D.C. 20057,¹ Institut für Zellbiologie, Ludwig-Maximilians-Universität München, 80336 München, Germany,² Department of Biology and Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom,³ Abt. Zellbiologie, Universität Kassel, 34132 Kassel, Germany,⁴ Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom,⁵ Centre for Molecular Cell Biology, Royal Free and University College London Medical School, London NW3 2PF, United Kingdom,⁶ Laboratories of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852⁷

Received 12 April 2006/ Accepted 4 March 2007

Valproic acid (VPA) is used to treat epilepsy and bipolar disorder and to prevent migraine. It is also undergoing trials for cancer therapy. However, the biochemical and molecular biological actions of VPA are poorly understood. Using the social amoeba Dictyostelium discoideum, we show that an acute effect of VPA is the inhibition of chemotactic cell movement, a process partially dependent upon phospholipid signaling. Analysis of this process shows that VPA attenuates the signal-induced translocation of PH_Crac-green fluorescent protein from cytosol to membrane, suggesting the inhibition of phosphatidylinositol-(3,4,5)-trisphosphate (PIP₃) production. Direct labeling of lipids in vivo also shows a reduction in PIP and PIP₂ phosphorylation following VPA treatment. We further show that VPA acutely reduces endocytosis and exocytosis—processes previously shown to be dependent upon PIP₃ production. These results suggest that in Dictyostelium, VPA rapidly attenuates phospholipid signaling to reduce endocytic trafficking. To examine this effect in a mammalian model, we also tested depolarization-dependent neurotransmitter release in rat nerve terminals, and we show that this process is also suppressed upon application of VPA and an inhibitor of phosphatidylinositol 3-kinase. Although a more comprehensive analysis of the effect of VPA on lipid signaling will be necessary in mammalian systems, these results suggest that VPA may function to reduce phospholipid signaling processes and thus may provide a novel therapeutic effect for this drug.

Published ahead of print on 13 April 2007.

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