Article ID Journal Published Year Pages File Type
2042138 Cell Reports 2014 12 Pages PDF
Abstract

•Slack KCNT1 mutations are found in three different epilepsy syndromes•Abnormal interactions between individual mutants greatly increase K+ current•Cooperativity enhances K+ current even in a mutant with reduced channel conductance•The same mutation can produce different forms of epilepsy in different individuals

SummaryDisease-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.

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