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Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid

Xu, XH; Muller-Taubenberger, A; Adley, KE; Pawolleck, N; Lee, VWY; Wiedemann, C; Sihra, TS; ... Williams, RSB; + view all (2007) Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid. EUKARYOT CELL , 6 (6) 899 - 906. 10.1128/EC.00104-06.

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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 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.

Type: Article
Title: Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid
DOI: 10.1128/EC.00104-06
Keywords: DICTYOSTELIUM-DISCOIDEUM, HISTONE DEACETYLASE, IN-VIVO, PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE, NEUROTRANSMITTER RELEASE, NEUTROPHIL CHEMOTAXIS, STATUS EPILEPTICUS, NEURONAL GROWTH, MOOD STABILIZER, DISTINCT ROLES
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/129472
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