Hydrophobic Drug/Toxin Binding Sites in Voltage-Dependent K and Na Channels.

In the Na channel family the lipophilic drugs/toxins binding sites and the presence of fenestrations in the channel pore wall are well defined and categorized. No such classification exists in the much larger K channel family, although certain lipophilic compounds seem to deviate from binding to well-known hydrophilic binding sites. By mapping different compound binding sites onto 3D structures of Kv channels, there appear to be three distinct lipid-exposed binding sites preserved in K channels: the front and back side of the pore domain, and S2-S3/S3-S4 clefts. One or a combination of these sites is most likely the orthologous equivalent of neurotoxin site 5 in Na channels. This review describes the different lipophilic binding sites and location of pore wall fenestrations within the K channel family and compares it to the knowledge of Na channels.