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Disease-causing mutations in ion channels generally alter intrinsic gating properties such as activation, inactivation, and voltage dependence. We examined nine different mutations of the KCNT1 (Slack) Na(+)-activated K(+) channel that give rise to three distinct forms of epilepsy. All produced many-fold increases in current amplitude compared to the wild-type channel. This could not be accounted for by increases in the intrinsic open probability of individual channels. Rather, greatly increased opening was a consequence of cooperative interactions between multiple channels in a patch. The degree of cooperative gating was much greater for all of the mutant channels than for the wild-type channel, and could explain increases in current even in a mutant with reduced unitary conductance. We also found that the same mutation gave rise to different forms of epilepsy in different individuals. Our findings indicate that a major consequence of these mutations is to alter channel-channel interactions.

Original publication




Journal article


Cell Rep

Publication Date





1661 - 1672


Animals, Cells, Cultured, Child, Preschool, Epilepsy, Gene Expression, Humans, Infant, Infant, Newborn, Mutation, Missense, Nerve Tissue Proteins, Point Mutation, Potassium Channels, Rats, Xenopus laevis