ABSTRACT
Small-conductance Ca2+-activated K+ (SK) channels mediate Ca2+-induced membrane hyperpolarization to fine-tune excitability. Their Ca2+ sensitivity stems from the Ca2+ binding protein calmodulin that is constitutively associated with the cytoplasmic C-terminus of the pore-forming channel alpha subunit. Upon binding of Ca2+, the calmodulin N-lobe contacts the S4–S5 linker and opens the channel gate. In addition to their critical role in regulating neuronal firing frequency, SK channels are involved in cardiac repolarization and endothelium-derived hyperpolarization in the vasculature. In keeping with these important physiological roles, the pharmacology of SK channels is relatively well characterized. Several venom peptides and cyclophane-type small molecules potently inhibit the channels from the extracellular side, while several chemotypes of small molecules act as gating modulators by either enhancing or dampening channel activity through changing the apparent Ca2+ sensitivity. Animal models have found these modulators beneficial for ataxias, essential tremor, alcohol use disorder and atrial fibrillation. Two SK channel modulators are currently being actively evaluated in clinical trials for the treatment of ataxia and atrial fibrillation.
