Antiepileptic teratogen valproic acid (VPA) modulates organisation and dynamics of the actin cytoskeleton

The antiepileptic drug valproic acid (VPA) and teratogenic VPA analogues ha ve been demonstrated to inhibit cell motility and affect cell morphology. W e here show that disruption of microtubules or of microfilaments by exposur e to nocodazole or cytochalasin D had different effects on morphology of co ntrol cells and cells treated with VPA, indicating that VPA affected the cy toskeletal determinants of cell morphology. Furthermore, VPA treatment indu ced an increase of F-actin, and of FAK, paxillin, vinculin, and phosphotyro sine in focal adhesion complexes. These changes were accompanied by increas ed adhesion of VPA-treated cells to the extracellular matrix, Treatment wit h an RGD-containing peptide reducing integrin binding to components of the extracellular matrix partially reverted the motility inhibition induced by VPA, indicating that altered adhesion contributed to, but was not the sole reason for the VPA mediated inhibition of motility. In addition it is shown that the actomyosin cytoskeleton of VPA-treated cells was capable of contr action upon exposure to ATP, indicating that the reduced motility of VPA-tr eated cells was not caused by an inhibition of actomyosin contraction. On t he other hand, VPA caused a redistribution of the actin severing protein ge lsolin, and left the cells unable to respond to treatment with a gelsolin-p eptide known to reduce the amount of gelsolin bound to phosphatidylinositol bisphosphate (PIP2), leaving a larger amount of the protein in a potential actin binding state. These findings indicate that VPA affects cell morphol ogy and motility through interference with the dynamics of the actin cytosk eleton. Cell Motil. Cytoskeleton 42:241-255, 1999. (C) 1999 Wiley-Liss, Inc .