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Coupling stabilizers open KV1-type potassium channels

Significance Voltage-gated ion channels are transmembrane pores responsible for the generation and transmission of nervous impulses. They are also obvious targets for pharmaceutical drugs against neurological diseases. A challenge is to develop compounds that target a specific ion channel. Here, we report on the discovery of a large family of compounds that specifically open one subfamily of potassium channels. These compounds act on the linker between the channel’s voltage sensor and gate to keep the channel open. These findings open up an avenue for the development of ion-channel modulators. The opening and closing of voltage-gated ion channels are regulated by voltage sensors coupled to a gate that controls the ion flux across the cellular membrane. Modulation of any part of gating constitutes an entry point for pharmacologically regulating channel function. Here, we report on the discovery of a large family of warfarin-like compounds that open the two voltage-gated type 1 potassium (KV1) channels KV1.5 and Shaker, but not the related KV2-, KV4-, or KV7-type channels. These negatively charged compounds bind in the open state to positively charged arginines and lysines between the intracellular ends of the voltage-sensor domains and the pore domain. This mechanism of action resembles that of endogenous channel-opening lipids and opens up an avenue for the development of ion-channel modulators.