Hollingworth, Dave and Thomas, Frances and Page, D.A. and Fouda, M.A. and Lopez-Rios De Castro, R. and Sula, A. and Mykhaylyk, V.B. and Kelly, G. and Ulmschneider, M.B. and Ruben, P.C. and Wallace, Bonnie (2024) Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole. Nature Communications 15 (1), p. 8426. ISSN 2041-1723.
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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 (INaL). INaL 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 INaL 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 INaL without the physical block of Na+ 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 INaL 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.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Depositing User: | Administrator |
| Date Deposited: | 04 Nov 2024 14:03 |
| Last Modified: | 05 Nov 2024 09:50 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/54501 |
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