Journal article
A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy
Biochemical Pharmacology, Vol.181, pp.1-15
2020
Abstract
Dravet syndrome (DS) is a catastrophic epileptic encephalopathy characterised by childhood-onset polymorphicseizures, multiple neuropsychiatric comorbidities, and increased risk of sudden death. Heterozygous loss-of-function mutations in one allele ofSCN1A, the gene encoding the voltage-gated sodium channel 1.1 (NaV1.1),lead to DS. NaV1.1 is primarily found in the axon initial segment of fast-spiking GABAergic inhibitory inter-neurons in the brain, and the principle mechanism proposed to underlie seizure genesis in DS is loss of inhibitoryinput due to dysfunctionalfiring of GABAergic interneurons. We hypothesised that DS symptoms could beameliorated by a drug that activates the reduced population of functional NaV1.1 channels in DS interneurons.We recently identified two homologous disulfide-rich spider-venom peptides (Hm1a and Hm1b) that selectivelypotentiate NaV1.1, and showed that selective activation of NaV1.1 by Hm1a restores the function of inhibitoryinterneurons in a mouse model of DS. Here we produced recombinant Hm1b (rHm1b) using anE. coliperi-plasmic expression system, and examined its selectivity against a panel of human NaVsubtypes using whole-cellpatch-clamp recordings. rHm1b is a potent and highly selective agonist of NaV1.1 and NaV1.3 (EC50~12 nM forboth). rHm1b is a gating modifier that shifts the voltage dependence of channel activation and inactivation tohyperpolarised 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 inhibitorcystine knot (ICK) motif. However, we show that rHm1b is an order of magnitude more stable than Hm1a inhuman cerebrospinalfluid. Overall, our data suggest that rHm1b is an exciting lead for a precision therapeutictargeted against DS.
Details
- Title
- A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy
- Authors
- Chun Yuen Chow (Author) - University of QueenslandYanni K Y Chin (Author) - University of QueenslandLinlin Ma (Author) - University of QueenslandEivind A B Undheim (Author) - University of QueenslandVolker Herzig (Author) - University of the Sunshine Coast - School of Science and EngineeringGlenn F King (Author) - University of Queensland
- Publication details
- Biochemical Pharmacology, Vol.181, pp.1-15
- Publisher
- Elsevier Inc.
- Date published
- 2020
- DOI
- 10.1016/j.bcp.2020.113991
- ISSN
- 0006-2952; 0006-2952
- 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
- 99451420102621
- Output Type
- Journal article
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