A recent study identified 28 novel genes with a high burden of de novo mutations associated with developmental disorders [1]. One of these genes was KCNK3 which encodes TASK-1 , a member of the Two-Pore Domain (K2P) family of K+ channels. The recent crystal structure of TASK-1 revealed a lower gate (X-gate) created by two crossed transmembrane helices (M4) at the vestibule entrance [2]. All nine patients in this cohort were heterozygous for a single de novo missense mutation in KCNK3 and shared a common phenotype with developmental delay, abnormality of the limbs, face and jaw, and also sleep apnea. A total of six unique mutations were found in this cohort of nine patients. TASK-1 is expressed in many tissues associated with sleep apnea and has previously been implicated in many of the pathways which control breathing, chemosensitivity and oxygen sensing [3, 4]. In this study, we investigated the functional properties of the six novel mutations found in these patients to gain a deeper insight into the mechanisms which produce sleep apnea and potential therapeutic strategies. Whole-cell recordings of heterologously expressed mutant TASK-1 channels revealed a markedly higher activity compared to wild-type TASK-1 with single channel recordings demonstrating up to a 10-fold increase in open probability for all the tested mutants. All six patient mutations are located within the M2 or M4 helices and cluster around the X-gate in TASK-1. Molecular dynamics simulations of both WT and mutant structures of TASK-1 also revealed that the mutations promote opening of the X-gate. Furthermore, both coexpression with G-protein coupled receptors (GPCR) and activation of endogenous muscarinic receptors revealed a strongly reduced sensitivity to GPCR-mediated inhibition of all mutant channel currents compared to wild type. Overall these mutations give rise to a marked gain-of-function compared to wild-type TASK-1 and so we characterised a wide range of natural ligands and drugs known to inhibit TASK-1 that might be used as a potential treatment for these patients. Nearly all known TASK-1 inhibitors were found to work equally well on these mutants, including one specific drug (BAY1000493) used in clinical trials for the treatment of sleep apnea which exhibits highly efficacious block of these mutant channels in the nanomolar range.
Physiology 2021 (2021) Proc Physiol Soc 48, PC091
Poster Communications: Defective X-gating in the TASK-1 K+ channel caused by de novo mutations in KCNK3 produces a developmental disorder with sleep apnea
Janina Sörmann1, Marcus Schewe2, Peter Proks1, Shanlin Rao3, Thibault Jouen-Tachoire1, Thomas Müller4, Thomas Baukrowitz2, Matthew E. Hurles5, Caroline F. Wright6, Stephen J. Tucker1
1 Department of Physics, University of Oxford, Oxford, United Kingdom 2 Institute of Physiology, Christian-Albrechts University of Kiel, Kiel, Germany 3 Department of Biochemistry, University of Oxford, Oxford, UK, Oxford, United Kingdom 4 Bayer AG, Research & Development, Pharmaceuticals, Wuppertal, Germany 5 Human Wellcome Sanger Genetics Programme, Institute, Wellcome Genome Campus, Hinxton, United Kingdom 6 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, United Kingdom
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Where applicable, experiments conform with Society ethical requirements.