Cole, BA, Clapcote, SJ, Muench, SP et al. (1 more author) (2021) Targeting KNa1.1 channels in KCNT1-associated epilepsy. Trends in Pharmacological Sciences. ISSN 0165-6147
Abstract
Gain-of-function (GOF) pathogenic variants of KCNT1, the gene encoding the largest known potassium channel subunit, KNa1.1, are associated with developmental and epileptic encephalopathies accompanied by severe psychomotor and intellectual disabilities. Blocking hyperexcitable KNa1.1 channels with quinidine, a class I antiarrhythmic drug, has shown variable success in patients in part because of dose-limiting off-target effects, poor blood–brain barrier (BBB) penetration, and low potency. In recent years, high-resolution cryogenic electron microscopy (cryo-EM) structures of the chicken KNa1.1 channel in different activation states have been determined, and animal models of the diseases have been generated. Alongside increasing information about the functional effects of GOF pathogenic variants on KNa1.1 channel behaviour and how they lead to hyperexcitability, these tools will facilitate the development of more effective treatment strategies. We review the range of KCNT1 variants and their functional effects, the challenges posed by current treatment strategies, and recent advances in finding more potent and selective therapeutic interventions for KCNT1-related epilepsies.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 Elsevier Ltd. All rights reserved. This is an author produced version of an article published in Trends in Pharmacological Sciences. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | epilepsy; EIMFS; (AD)SHE; KCNT1; KNa1.1; potassium channel |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 03 Jun 2021 11:41 |
Last Modified: | 29 May 2022 00:38 |
Status: | Published online |
Publisher: | Cell Press |
Identification Number: | 10.1016/j.tips.2021.05.003 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:174791 |