当前位置： SCI文献检索 > BIOCHEMICAL PHARMACOLOGY期刊下所有文献 > A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy.

A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy.

Abstract：

: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 (NaV1.1), lead to DS. NaV1.1 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 NaV1.1 channels in DS interneurons. We recently identified two homologous disulfide-rich spider-venom peptides (Hm1a and Hm1b) that selectively potentiate NaV1.1, and showed that selective activation of NaV1.1 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 NaV subtypes using whole-cell patch-clamp recordings. rHm1b is a potent and highly selective agonist of NaV1.1 and NaV1.3 (EC50 ~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.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Chow CY,Chin YKY,Ma L,Undheim EAB,Herzig V,King GF

doi

10.1016/j.bcp.2020.113991

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

113991

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(20)30219-7

journal_volume

181

pub_type

杂志文章

在线工具

A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy.