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MBC in Press, published online ahead of print February 20, 2008
Mol. Biol. Cell 10.1091/mbc.E07-09-0982

A more recent version of this article appeared on May 1, 2008
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Submitted on September 28, 2007
Revised on February 5, 2008
Accepted on February 13, 2008

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

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

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

Monitoring Editor: Tom U. Martin

The anti-epileptic 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 C.elegans. VPA disrupts two behaviors regulated by the inositol 1,4,5-Tris phosphate (IP3): defecation and ovulation. VPA also inhibits two activities regulated by DAG signaling: acetylcholine (ACh) release and egg-laying. The effects of VPA on DAG signaling are relieved by phorbol ester, a DAG analog, suggesting that VPA acts to inhibit DAG production. VPA reduces levels of DAG and IP1, but PIP2 is slightly increased, suggesting that Phospholipase C mediated hydrolysis of PIP2 to form DAG and IP3 is defective in the presence of VPA.

*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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