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Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.
- Source :
-
Nature communications [Nat Commun] 2024 Sep 28; Vol. 15 (1), pp. 8426. Date of Electronic Publication: 2024 Sep 28. - Publication Year :
- 2024
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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).)
- Subjects :
- Humans
Voltage-Gated Sodium Channels metabolism
Voltage-Gated Sodium Channels chemistry
HEK293 Cells
Animals
Sodium metabolism
Motor Neurons drug effects
Motor Neurons metabolism
Riluzole pharmacology
Amyotrophic Lateral Sclerosis drug therapy
Amyotrophic Lateral Sclerosis metabolism
Amyotrophic Lateral Sclerosis genetics
Neuroprotective Agents pharmacology
Subjects
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