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
Affiliations
Grace E. Kim
Department of Pharmacology, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA
Jack Kronengold
Department of Pharmacology, Yale University, New Haven, CT 06520, USA
Giulia Barcia
Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France
Imran H. Quraishi
Comprehensive Epilepsy Center, Department of Neurology, Yale University, New Haven, CT 06520, USA
Hilary C. Martin
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Edward Blair
Oxford University Hospitals Trust, Oxford OX3 9DU, UK
Jenny C. Taylor
Oxford Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Olivier Dulac
Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France
Laurence Colleaux
INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, 75015 Paris, France
Rima Nabbout
Department of Pediatric Neurology, Centre de Reference Epilepsies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France
Leonard K. Kaczmarek
Department of Pharmacology, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA; Corresponding author
Summary: 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 et al. 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.
