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 (K_V1) channels K_V1.5 and Shaker, but not the related K_V2-, K_V4-, or K_V7-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.

电压门控离子通道的打开和关闭由耦合到控制细胞膜上离子通量的栅极的电压传感器调节。门控任何部分的调制构成了药理调节通道功能的切入点。在这里，我们报告了发现一大类类似华法令的化合物的发现，这些化合物打开了两个电压门控的1型钾离子（K _V 1）通道K _V 1.5和Shaker，但没有打开相关的K _V 2-，K _V 4 -或K _V7型通道。这些带负电荷的化合物在开放状态下与电压传感器结构域和孔结构域的细胞内末端之间的带正电荷的精氨酸和赖氨酸结合。这种作用机制类似于内源性开放通道脂质，并为开发离子通道调节剂开辟了一条途径。