The cardiac sodium ion channel (NaV1.5) is a protein with four domains (DI-DIV), each
with six transmembrane segments. Its opening and subsequent inactivation results in the brief rapid
influx of Na+ ions resulting in the depolarization of cardiomyocytes. The neurotoxin veratridine
(VTD) inhibits NaV1.5 inactivation resulting in longer channel opening times, and potentially fatal
action potential prolongation. VTD is predicted to bind at the channel pore, but alternative binding
sites have not been ruled out. To determine the binding site of VTD on NaV1.5, we perform docking
calculations and high-throughput electrophysiology experiments in the present study. The docking
calculations identified two distinct binding regions. The first site was in the pore, close to the
binding site of NaV1.4 and NaV1.5 blocking drugs in experimental structures. The second site was at
the “mouth” of the pore at the cytosolic side, partly solvent-exposed. Mutations at this site (L409,
E417, and I1466) had large effects on VTD binding, while residues deeper in the pore had no effect,
consistent with VTD binding at the mouth site. Overall, our results suggest a VTD binding site
close to the cytoplasmic mouth of the channel pore. Binding at this alternative site might indicate an
allosteric inactivation mechanism for VTD at NaV1.5
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89165 |
| Date | 20 January 2024 |
| Creators | Gulsevin, Alican, Glazer, Andrew M., Shields, Tiffany, Kroncke, Brett M., Roden, Dan M., Meiler, Jens |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2225 |
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