Volatile anaesthetics modulate voltage-gated sodium channel function at a site directly linked to channel gating.

Summary

This mechanistic study defines an atomic-resolution binding pocket for sevoflurane in a voltage-gated sodium channel and links this site to modulation of fast and slow inactivation. Mutation of a conserved tyrosine abolishes sevoflurane binding and its hyperpolarizing shift of steady-state inactivation, with supportive evidence across prokaryotic and human channels.

Key Findings

• Identified an atomic-resolution sevoflurane binding pocket in NavMs that displaces membrane lipid.
• Substitution of an invariant tyrosine abolishes sevoflurane binding and its hyperpolarizing shift of steady-state inactivation.
• Sevoflurane modulates both fast and slow inactivation in human Nav1.1, with evidence for homologous binding sites in human VGSCs.
• Multiple volatile anesthetics share binding sites on prokaryotic VGSCs, supporting a membrane-assisted gating modulation pathway.

Clinical Implications

While preclinical, defining a conserved VA binding site on VGSCs refines mechanistic understanding of anesthesia and may enable development of agents with improved safety or targeted channel modulation (e.g., minimizing neurotoxicity or dysrhythmias).

Limitations

• Primary structural work in a prokaryotic VGSC may not capture full complexity of mammalian channels in native membranes.
• No in vivo demonstration of network-level or behavioral effects tied to the identified site.

Future Directions

Validate homologous binding in diverse human VGSC isoforms in native systems, and leverage structure to design channel subtype-selective anesthetics with optimized safety profiles.