Potassium channel openers targeting different sites of the channel.

Abstract

Voltage-gated ion channels play essential roles in generating and shaping the electrical excitability of nerve and heart cells. Mutations in these ion channels can cause diseases, which can be treated with pharmaceuticals targeting specific ion channels. While many pharmaceuticals cause their effects by blocking the ion-conducting pore to prevent the ion current, only a few exert their therapeutic effect by opening (or activating) the channel. While they see limited use as pharmaceuticals at present, recent research has identified many different types of compounds that can open ion channels. Here, I will present data from three classes of compounds capable of opening voltage-gated potassium (Kv) channels. (1) The first class includes resin acids and polyunsaturated fatty acids. These negatively charged compounds have close interactions with the channel's positively charged voltage sensor, opening the channel by pulling the sensor to an activated position. This interaction occurs at the interface between the phospholipid bilayer and the channel protein. (2) Biaryl sulfonamide acids can access the voltage sensor through the extracellular space, allowing them to activate the Kv1-like Shaker channel. (3) Warfarine-like tautomers activate Kv1.5 channels via close interactions with the linker connecting the voltage sensor and the channel's ion conducting pore domain. Characterizing different binding sites and compounds that use them on different ion channels will hopefully lead to better treatments for diseases caused by altered excitability.