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Originally published as MBC in Press, 10.1091/mbc.E07-09-0982 on February 20, 2008

Vol. 19, Issue 5, 2241-2250, May 2008

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The Mood Stabilizer Valproate Inhibits both Inositol- and Diacylglycerol-signaling Pathways in Caenorhabditis elegans

Suzumi M. Tokuoka*,{dagger}, Adolfo Saiardi{ddagger}, and Stephen J. Nurrish{dagger}

MRC Cell Biology Unit, MRC Laboratory for Molecular Cell Biology, {dagger}Departments of Neuroscience, Physiology, and Pharmacology and {ddagger}Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom

Submitted September 28, 2007; Revised February 5, 2008; Accepted February 13, 2008
Monitoring Editor: Thomas F. J. Martin

The antiepileptic valproate (VPA) is widely used in the treatment of bipolar disorder, although the mechanism of its action in the disorder is unclear. We show here that VPA inhibits both inositol phosphate and diacylglycerol (DAG) signaling in Caenorhabditis elegans. VPA disrupts two behaviors regulated by the inositol-1,4,5-trisphosphate (IP3): defecation and ovulation. VPA also inhibits two activities regulated by DAG signaling: acetylcholine release and egg laying. The effects of VPA on DAG signaling are relieved by phorbol ester, a DAG analogue, suggesting that VPA acts to inhibit DAG production. VPA reduces levels of DAG and inositol-1-phosphate, but phosphatidylinositol-4,5-bisphosphate (PIP2) is slightly increased, suggesting that phospholipase C-mediated hydrolysis of PIP2 to form DAG and IP3 is defective in the presence of VPA.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-09-0982) on February 20, 2008.

* Present address: Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Address correspondence to: Stephen J. Nurrish (s.nurrish{at}ucl.ac.uk)






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