The three small-conductance calcium-activated potassium (KCa2) channels and the related intermediate-conductance KCa3.1 channel are voltage-independent K+ channels that mediate calcium-induced membrane hyperpolarization. When intracellular calcium increases in the channel vicinity, it calcifies the flexible N lobe of the channel-bound calmodulin, which then swings over to the S4-S5 linker and opens the channel. KCa2 and KCa3.1 channels are highly druggable and offer multiple binding sites for venom peptides and small-molecule blockers as well as for positive- and negative-gating modulators. In this review, we briefly summarize the physiological role of KCa channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule KCa2 and KCa3.1 modulators. Finally, we describe the progress that has been made in advancing KCa3.1 blockers and KCa2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges.

中文翻译：

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中小电导钙激活钾通道的药理学。

三个小电导钙激活钾 (KCa2) 通道和相关的中间电导 KCa3.1 通道是介导钙诱导的膜超极化的电压非依赖性 K+ 通道。当细胞内钙在通道附近增加时，它会钙化通道结合钙调蛋白的柔性 N 叶，然后转向 S4-S5 接头并打开通道。KCa2 ​​和 KCa3.1 通道具有高度的成药性，并为毒液肽和小分子阻滞剂以及正门控和负门控调节剂提供多个结合位点。在这篇综述中，我们简要总结了 KCa 通道的生理作用，然后讨论了最常用的肽和小分子 KCa2 ​​和 KCa3.1 调节剂的药效团和作用机制。最后，