| Autor: |
Terbach N; Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham TW200EX, UK., Shah R, Kelemen R, Klein PS, Gordienko D, Brown NA, Wilkinson CJ, Williams RS |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of cell science [J Cell Sci] 2011 Jul 01; Vol. 124 (Pt 13), pp. 2267-76. Date of Electronic Publication: 2011 Jun 07. |
| DOI: |
10.1242/jcs.084285 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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