This short review discusses pharmacological modulation of the opening/closing properties (gating) of small- and intermediate-conductance Ca(2+)-activated K(+) channels (KCa2 and KCa3.1) with special focus on mechanisms-of-action, selectivity, binding sites, and therapeutic potentials. Despite KCa channel gating-modulation being a relatively novel field in drug discovery, efforts in this area have already revealed a surprising plethora of pharmacological sites-of-actions and channel subtype selectivity exerted by different chemical classes. The currently published positive modulators show that such molecules are potentially useful for the treatment of various neurodegenerative disorders such as ataxia, alcohol dependence, and epilepsy as well as hypertension. The negative KCa2 modulators are very effective agents for atrial fibrillation. The prediction is that further unraveling of the molecular details of gating pharmacology will allow for the design of even more potent and subtype selective KCa modulators entering into drug development for these indications.
Keywords: Ca2+-activated K+ channel; CyPPA; IK channel; KCa2; KCa3.1; NS309; SK channel; SKA-121; SKA-31.