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Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.

Authors :
Hollingworth D
Thomas F
Page DA
Fouda MA
De Castro RL
Sula A
Mykhaylyk VB
Kelly G
Ulmschneider MB
Ruben PC
Wallace BA
Source :
Nature communications [Nat Commun] 2024 Sep 28; Vol. 15 (1), pp. 8426. Date of Electronic Publication: 2024 Sep 28.
Publication Year :
2024

Abstract

Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (I <subscript>NaL</subscript> ). I <subscript>NaL</subscript> results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of I <subscript>NaL</subscript> that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of I <subscript>NaL</subscript> without the physical block of Na <superscript>+</superscript> conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased I <subscript>NaL</subscript> is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing.<br /> (© 2024. The Author(s).)

Details

Language :
English
ISSN :
2041-1723
Volume :
15
Issue :
1
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
39341837
Full Text :
https://doi.org/10.1038/s41467-024-52539-4