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Human slack potassium channel mutations increase positive cooperativity between individual channels.

Authors
  • Blair, Edward
  • Taylor, Jenny C
  • Dulac, Olivier
  • Laurence Colleaux
  • Nabbout, Rima
  • Kaczmarek, Leonard K
  • Kim, Grace E
  • Kronengold, Jack
  • Barcia, Giulia
  • Quraishi, Imran H
  • Martin, Hilary C
Type
Published Article
Journal
Cell Host & Microbe
Publisher
Elsevier
Publication Date
Dec 11, 2014
Volume
9
Issue
5
Pages
1661–1672
Identifiers
DOI: 10.1016/j.celrep.2014.11.015
PMID: 25482562
Source
USPC - SET - SVS
License
Unknown

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.

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