Journal article
Venom Peptides with Dual Modulatory Activity on the Voltage-Gated Sodium Channel NaV1.1 Provide Novel Leads for Development of Antiepileptic Drugs
ACS Pharmacology & Translational Science, Vol.3, pp.119-134
2020
Abstract
Voltage-gated sodium (NaV) channels play a fundamental role in normal neurological function, especially via the initiation and propagation of action potentials. The NaV1.1 subtype is found in inhibitory interneurons of the brain and it is essential for maintaining a balance between excitation and inhibition in neuronal networks. Heterozygous loss-of-function mutations of SCN1A, the gene encoding NaV1.1, underlie Dravet syndrome (DS), a severe pediatric epilepsy. We recently demonstrated that selective inhibition of NaV1.1 inactivation prevents seizures and premature death in a mouse model of DS. Thus, selective modulators of NaV1.1 might be useful therapeutics for treatment of DS as they target the underlying molecular deficit. Numerous scorpion-venom peptides have been shown to modulate the activity of NaV channels, but little is known about their activity at NaV1.1. Here we report the isolation, sequence, three-dimensional structure, recombinant production, and functional characterization of two peptidic modulators of NaV1.1 from venom of the buthid scorpion Hottentotta jayakari. These peptides, Hj1a and Hj2a, are potent agonists of NaV1.1 (EC50 of 17 and 32 nM, respectively), and they present dual α/β activity by modifying both the activation and inactivation properties of the channel. NMR studies of rHj1a indicate that it adopts a cystine-stabilized αβ fold similar to known scorpion toxins. Although Hj1a and Hj2a have only limited selectivity for NaV1.1, their unusual dual mode of action provides an alternative approach to the development of selective NaV1.1 modulators for the treatment of DS.
Details
- Title
- Venom Peptides with Dual Modulatory Activity on the Voltage-Gated Sodium Channel NaV1.1 Provide Novel Leads for Development of Antiepileptic Drugs
- Authors
- Chun Yeun Chow (Author) - University of QueenslandYanni K-Y Chin (Author) - University of QueenslandAndrew A Walker (Author) - University of QueenslandShaodong Guo (Author) - University of QueenslandLinda V Blomster (Author) - University of QueenslandMicaiah J Ward (Author) - Florida State University, United StatesVolker Herzig (Author) - University of QueenslandDarin R Rokyta (Author) - Florida State University, United StatesGlenn F King (Author) - University of Queensland
- Publication details
- ACS Pharmacology & Translational Science, Vol.3, pp.119-134
- Publisher
- American Chemical Society
- Date published
- 2020
- DOI
- 10.1021/acsptsci.9b00079
- ISSN
- 2575-9108
- Copyright note
- Copyright © 2019 American Chemical Society. This article is made available for a limited time sponsored by ACS under the ACS Free to Read License, which permits copying and redistribution of the article for non-commercial scholarly purposes.
- Organisation Unit
- School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99451328202621
- Output Type
- Journal article
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- Chemistry, Medicinal
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