title: Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid.
abstract: 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 (PIP(3)) production. Direct labeling of lipids in vivo also shows a reduction in PIP and PIP(2) phosphorylation following VPA treatment. We further show that VPA acutely reduces endocytosis and exocytosis-processes previously shown to be dependent upon PIP(3) 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.
authors: School of Biological Sciences, Royal Holloway University of London, Egham, United Kingdom.
authors: Xuehua
authors: X
authors: Xu
authors: Annette
authors: A
authors: Müller-Taubenberger
authors: Kathryn E
authors: KE
authors: Adley
authors: Nadine
authors: N
authors: Pawolleck
authors: Vivian W Y
authors: VW
authors: Lee
authors: Claudia
authors: C
authors: Wiedemann
authors: Talvinder S
authors: TS
authors: Sihra
authors: Markus
authors: M
authors: Maniak
authors: Tian
authors: T
authors: Jin
authors: Robin S B
authors: RS
authors: Williams
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D004023:Dictyostelium / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004705:Endocytosis / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005089:Exocytosis / Q000502:physiology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014635:Valproic Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D010743:Phospholipids; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; C089420:dagA protein, Dictyostelium; D014635:Valproic Acid; D015544:Inositol 1,4,5-Trisphosphate; D019869:Phosphatidylinositol 3-Kinases