Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels

The three small-conductance calcium-activated potassium (K Ca 2) channels and the related intermediate-conductance K Ca 3.1 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. K Ca 2 and K Ca 3.1 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 K Ca channels and then discuss the pharmacophores and the mechanism of action of the most commonly used peptidic and small-molecule K Ca 2 and K Ca 3.1 modulators. Finally, we describe the progress that has been made in advancing K Ca 3.1 blockers and K Ca 2.2 negative- and positive-gating modulators toward the clinic for neurological and cardiovascular diseases and discuss the remaining challenges.