The mood stabilizer valproate inhibits both inositol- and diacylglycerol-signaling pathways in Caenorhabditis elegans.
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 (IP(3)): 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 (PIP(2)) is slightly increased, suggesting that phospholipase C-mediated hydrolysis of PIP(2) to form DAG and IP(3) is defective in the presence of VPA.
Tokuoka
Suzumi M
SM
MRC Cell Biology Unit, MRC Laboratory for Molecular Cell Biology, Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
Saiardi
Adolfo
A
Nurrish
Stephen J
SJ
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002352:Carrier Proteins; D003672:Defecation / Q000187:drug effects; D004075:Diglycerides / Q000378:metabolism*; D007294:Inositol / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D010060:Ovulation / Q000187:drug effects; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology*
C011439:1,2-diacylglycerol; D018692:Antimanic Agents; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D004075:Diglycerides; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007295:Inositol Phosphates; D019269:Phosphatidylinositol 4,5-Diphosphate; C083141:phorbol ester binding protein; C002647:inositol 1-phosphate; D007294:Inositol; D014635:Valproic Acid; D015544:Inositol 1,4,5-Trisphosphate; D000109:Acetylcholine