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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{triangledown} ,{dagger}

Xuehua Xu,1 Annette Müller-Taubenberger,2 Kathryn E. Adley,3 Nadine Pawolleck,4 Vivian W. Y. Lee,5 Claudia Wiedemann,6 Talvinder S. Sihra,5 Markus Maniak,4 Tian Jin,7 and Robin S. B. Williams3*

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 PHCrac-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.

* Corresponding author. Present address: School of Biological Sciences, Royal Holloway University of London, Egham TW20 0EX, United Kingdom. Phone: 44 178427 6162. Fax: 44 178441 4224. E-mail: robin.williams{at}rhul.ac.uk

{triangledown} Published ahead of print on 13 April 2007.

{dagger} Supplemental material for this article may be found at http://ec.asm.org/.

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.



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