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Tytuł:
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A selective Na V 1.1 activator with potential for treatment of Dravet syndrome epilepsy.
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Autorzy:
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Chow CY; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Chin YKY; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Ma L; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Undheim EAB; Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD 4072, Australia.
Herzig V; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
King GF; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: .
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Źródło:
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Biochemical pharmacology [Biochem Pharmacol] 2020 Nov; Vol. 181, pp. 113991. Date of Electronic Publication: 2020 Apr 23.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.
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MeSH Terms:
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Epilepsies, Myoclonic/*drug therapy
Interneurons/*drug effects
NAV1.1 Voltage-Gated Sodium Channel/*metabolism
Peptides/*pharmacology
Sodium Channel Agonists/*pharmacology
Action Potentials/drug effects ; Amino Acid Sequence ; Animals ; Disease Models, Animal ; Epilepsies, Myoclonic/metabolism ; HEK293 Cells ; Humans ; Interneurons/metabolism ; Mice ; NAV1.1 Voltage-Gated Sodium Channel/genetics ; Patch-Clamp Techniques ; Peptides/chemistry ; Peptides/genetics ; Sequence Homology, Amino Acid ; Sodium Channel Agonists/chemistry ; Spider Venoms/metabolism
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Contributed Indexing:
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Keywords: Dravet syndrome; Epilepsy; Na(V)1.1; Venom peptide; Voltage-gated sodium channel
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Substance Nomenclature:
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0 (NAV1.1 Voltage-Gated Sodium Channel)
0 (Peptides)
0 (SCN1A protein, human)
0 (Sodium Channel Agonists)
0 (Spider Venoms)
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Entry Date(s):
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Date Created: 20200427 Date Completed: 20210104 Latest Revision: 20210104
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Update Code:
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20240105
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DOI:
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10.1016/j.bcp.2020.113991
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PMID:
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32335140
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Dravet syndrome (DS) is a catastrophic epileptic encephalopathy characterised by childhood-onset polymorphic seizures, multiple neuropsychiatric comorbidities, and increased risk of sudden death. Heterozygous loss-of-function mutations in one allele of SCN1A, the gene encoding the voltage-gated sodium channel 1.1 (Na V 1.1), lead to DS. Na V 1.1 is primarily found in the axon initial segment of fast-spiking GABAergic inhibitory interneurons in the brain, and the principle mechanism proposed to underlie seizure genesis in DS is loss of inhibitory input due to dysfunctional firing of GABAergic interneurons. We hypothesised that DS symptoms could be ameliorated by a drug that activates the reduced population of functional Na V 1.1 channels in DS interneurons. We recently identified two homologous disulfide-rich spider-venom peptides (Hm1a and Hm1b) that selectively potentiate Na V 1.1, and showed that selective activation of Na V 1.1 by Hm1a restores the function of inhibitory interneurons in a mouse model of DS. Here we produced recombinant Hm1b (rHm1b) using an E. coli periplasmic expression system, and examined its selectivity against a panel of human Na V subtypes using whole-cell patch-clamp recordings. rHm1b is a potent and highly selective agonist of Na V 1.1 and Na V 1.3 (EC 50 ~12 nM for both). rHm1b is a gating modifier that shifts the voltage dependence of channel activation and inactivation to hyperpolarised and depolarised potentials respectively, presumably by interacting with the channel's voltage-sensor domains. Like Hm1a, the structure of rHm1b determined by using NMR revealed a classical inhibitor cystine knot (ICK) motif. However, we show that rHm1b is an order of magnitude more stable than Hm1a in human cerebrospinal fluid. Overall, our data suggest that rHm1b is an exciting lead for a precision therapeutic targeted against DS.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
