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

• Published in: Nature communications 2024-09, Vol.15 (1), p.8426-14, Article 8426
• Main Authors: Hollingworth, David, Thomas, Frances, Page, Dana A., Fouda, Mohamed A., De Castro, Raquel Lopez-Rios, Sula, Altin, Mykhaylyk, Vitaliy B., Kelly, Geoff, Ulmschneider, Martin B., Ruben, Peter C., Wallace, B. A.
• Format: Article
• Language: English
• Subjects: 140/131; 631/1647/1453/1970; 631/378/1689/1285; 631/535/1266; 631/535/1267; 9/97; Allosteric properties; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Binding sites; Cellular structure; Channel gating; Deactivation; Drug development; Excitability; HEK293 Cells; Humanities and Social Sciences; Humans; Inactivation; Membranes; Motor neuron diseases; Motor Neurons - drug effects; Motor Neurons - metabolism; multidisciplinary; Neurodegenerative diseases; Neuroprotection; Neuroprotective Agents - pharmacology; Physiological effects; Riluzole - pharmacology; Science; Science (multidisciplinary); Sodium; Sodium - metabolism; Sodium channels (voltage-gated); Voltage-Gated Sodium Channels - chemistry; Voltage-Gated Sodium Channels - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52539-4

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 NaL ). I NaL 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 NaL 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 NaL 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 I NaL 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. The authors here present a high-resolution structure of riluzole bound to a voltage-gated sodium channel. This identifies an intramembranous drug-binding site allowing the potent riluzole-induced enhancement of channel inactivation, normalising the hyperexcitable cellular states found in ALS models. This supports riluzole repurposing and aids future drug design efforts.