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Cell Rep. 2014 Dec 11;9(5):1661-72. doi: 10.1016/j.celrep.2014.11.015. Epub 2014 Dec 4.

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

Author information

1
Department of Pharmacology, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.
2
Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
3
Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
4
Comprehensive Epilepsy Center, Department of Neurology, Yale University, New Haven, CT 06520, USA.
5
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
6
Oxford University Hospitals Trust, Oxford OX3 9DU, UK.
7
Oxford Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
8
INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, 75015 Paris, France.
9
Department of Pharmacology, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA. Electronic address: leonard.kaczmarek@yale.edu.

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.

PMID:
25482562
PMCID:
PMC4294418
DOI:
10.1016/j.celrep.2014.11.015
[Indexed for MEDLINE]
Free PMC Article
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