Abstract
Valproic acid (VPA) is an anticonvulsant drug that is also used to treat migraines and bipolar disorder. Its proposed biological targets include human voltage-gated sodium channels, among other membrane proteins. We used the prokaryotic NavMs sodium channel, which has been shown to be a good exemplar for drug binding to human sodium channels, to examine the structural and functional interactions of VPA. Thermal melt synchrotron radiation circular dichroism spectroscopic binding studies of the full-length NavMs channel (which includes both pore and voltage sensor domains), and a pore-only construct, undertaken in the presence and absence of VPA, indicated that the drug binds to and destabilizes the channel, but not the poreonly construct. This is in contrast to other antiepileptic compounds that have previously been shown to bind in the central hydrophobic core of the pore region of the channel, and that tend to increase the thermal stability of both pore-only constructs and full-length channels. Molecular docking studies also indicated that the VPA binding site is associated with the voltage sensor, rather than the hydrophobic cavity of the pore domain. Electrophysiological studies show that VPA influences the block and inactivation rates of the NavMs channel, although with lower efficacy than classical channel-blocking compounds. It thus appears that, while VPA is capable of binding to these voltage-gated sodium channels, it has a very different mode and site of action than other anticonvulsant compounds.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 26549-26554 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 116 |
| Issue number | 52 |
| DOIs | |
| State | Published - Dec 26 2019 |
Funding
ACKNOWLEDGMENTS. This work was supported by Grants BB/L006790, BB/ P024092, BB/L026252, and BB/R001294 from the UK Biotechnology and Biological Science Research Council (to B.A.W.). G.Z. was supported by a Science Without Borders Fellowship from the Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnológico. P.G.D. was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (1R56DK119709-01 and 4R00DK106655), the American Society of Nephrology (Carl W. Gottschalk Scholar Award), and the Polycystic Kidney Disease Foundation. Docking calculations and molecular dynamics simulations by G.Z. were performed using resources from Centro Nacional de Processamento de Alto Desempenho–Universidade Federal do Ceará (Brazil) and Centro Nacional de Supercomputação–Universidade Federal do Rio Grande do Sul (Brazil). We thank Dr. Jennifer Booker for help with initial purification of the channel. This work was supported by Grants BB/L006790, BB/P024092, BB/L026252, and BB/R001294 from the UK Biotechnology and Biological Science Research Council (to B.A.W.). G.Z. was supported by a Science Without Borders Fellowship from the Brazilian Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico. P.G.D. was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (1R56DK119709-01 and 4R00DK106655), the American Society of Nephrology (Carl W. Gottschalk Scholar Award), and the Polycystic Kidney Disease Foundation. Docking calculations and molecular dynamics simulations by G.Z. were performed using resources from Centro Nacional de Processamento de Alto Desempenho-Universidade Federal do Cear? (Brazil) and Centro Nacional de Supercomputa??o-Universidade Federal do Rio Grande do Sul (Brazil). We thank Dr. Jennifer Booker for help with initial purification of the channel.
Keywords
- Drug binding
- Valproic acid
- Voltage-gated sodium channels
ASJC Scopus subject areas
- General