title: Identifying an uptake mechanism for the antiepileptic and bipolar disorder treatment valproic acid using the simple biomedical model Dictyostelium.
abstract: Valproic acid (VPA) is the most highly prescribed epilepsy treatment worldwide and is also used to prevent bipolar disorder and migraine. Surprisingly, very little is known about its mechanisms of cellular uptake. Here, we employ a range of cellular, molecular and genetic approaches to characterize VPA uptake using a simple biomedical model, Dictyostelium discoideum. We show that VPA is taken up against an electrochemical gradient in a dose-dependent manner. Transport is protein-mediated, dependent on pH and the proton gradient and shows strong substrate structure specificity. Using a genetic screen, we identified a protein homologous to a mammalian solute carrier family 4 (SLC4) bicarbonate transporter that we show is involved in VPA uptake. Pharmacological and genetic ablation of this protein reduces the uptake of VPA and partially protects against VPA-dependent developmental effects, and extracellular bicarbonate competes for VPA uptake in Dictyostelium. We further show that this uptake mechanism is likely to be conserved in both zebrafish (Danio rerio) and Xenopus laevis model systems. These results implicate, for the first time, an uptake mechanism for VPA through SLC4-catalysed activity.
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW200EX, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Terbach
authors.forename: Rishita
authors.initials: R
authors.lastname: Shah
authors.forename: Rachel
authors.initials: R
authors.lastname: Kelemen
authors.forename: Peter S
authors.initials: PS
authors.lastname: Klein
authors.forename: Dmitri
authors.initials: D
authors.lastname: Gordienko
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Brown
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilkinson
authors.forename: Robin S B
authors.initials: RS
authors.lastname: Williams
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D002478:Cells, Cultured; D004023:Dictyostelium / Q000187:drug effects / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D014635:Valproic Acid / Q000378:metabolism* / Q000494:pharmacology; D014982:Xenopus laevis; D015027:Zebrafish
chemical_list: D026901:Membrane Transport Proteins; D014635:Valproic Acid