Human Slack Potassium Channel Mutations Increase Positive Cooperativity between Individual Channels

Grace E. Kim, Jack Kronengold, Giulia Barcia, Imran H. Quraishi, Hilary C. Martin, Edward Blair, Jenny C. Taylor, Olivier Dulac, Laurence Colleaux, Rima Nabbout, Leonard K. Kaczmarek

Research output: Contribution to journalArticlepeer-review

Abstract

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. Slack KCNT1 channels regulate how neurons respond to sustained stimulation. Kim etal. characterized nine KCNT1 mutations found in epilepsy patients with severe intellectual disabilities and showed that, in isolation, channel behavior is unaltered. However, in groups, mutant channels interact with each other abnormally, increasing current that flows through the channels.

Original languageEnglish (US)
Pages (from-to)1661-1672
Number of pages12
JournalCell Reports
Volume9
Issue number5
DOIs
StatePublished - Dec 11 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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