Coupling stabilizers open Kv1-type potassium channels
Coupling stabilizers open Kv1-type potassium channels
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DOI：
10.1073/pnas.2007965117
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发表时间：
2020-10-27
影响因子：
11.1
通讯作者：
Elinder, Fredrik
中科院分区：
文献类型：
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作者：
Ejneby, Malin Silvera;Wallner, Bjorn;Elinder, Fredrik
电压门控离子通道的打开和关闭由与控制穿过细胞膜的离子通量的门耦合的电压传感器调节。门控任何部分的调节构成了药理学调节通道功能的切入点。在此，我们报告了一大类华法林类化合物的发现，这些化合物可打开两个电压门控 1 型钾 (K(v)1) 通道 K(v)1.5 和 Shaker，但不打开相关的 K(v)2-、K(v)4- 或 K(v)7- 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域和孔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通道开放脂质的作用机制，并为离子通道调节剂的开发开辟了途径。
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(v)1) channels K(v)1.5 and Shaker, but not the related K(v)2-, K(v)4-, or K(v)7-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.