Function and pharmacology of human Na+-activated K+ channels

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Inherited and spontaneous gain-of-function mutations in the human KCNT1 gene, which encodes the SLACK Na+-activated K+ channel, have recently been linked to severe and drug-resistant epilepsies. Children suffering from these disorders have poor quality of life and many do not survive to adulthood. Inhibiting this channel with a potent and selective small molecule therapeutic is therefore a prioritised strategy for the treatment of these epilepsies. The SLACK channel is a poorly studied and understood potassium channel, with the Leeds group one of only a handful of laboratories with experience in studying its function, pharmacology, and effects of mutations. Underpinning fundamental research is required to understand (a) how exactly the epilepsy-related mutations affect both the structure and function of the channel, and (b) the mechanism by which known inhibitors and activators exert their effects.