title: Human slack potassium channel mutations increase positive cooperativity between individual channels.
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.
authors.affiliation: Department of Pharmacology, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Kronengold
authors.affiliation: Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Barcia
authors.affiliation: Comprehensive Epilepsy Center, Department of Neurology, Yale University, New Haven, CT 06520, USA.
authors.forename: Imran H
authors.initials: IH
authors.lastname: Quraishi
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Hilary C
authors.initials: HC
authors.lastname: Martin
authors.affiliation: Oxford University Hospitals Trust, Oxford OX3 9DU, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Blair
authors.affiliation: Oxford Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Taylor
authors.affiliation: Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.affiliation: INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.affiliation: Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.affiliation: 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.
authors.forename: Leonard K
authors.initials: LK
authors.lastname: Kaczmarek
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D000081033:Potassium Channels, Sodium-Activated; D051381:Rats; D014982:Xenopus laevis
chemical_list: C585122:KCNT1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated