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Molecular Basis of Sodium Channel Inactivation
Preprint   Open access

Molecular Basis of Sodium Channel Inactivation

Yichen Liu, Jason Galpin, Christopher A Ahern and Francisco Bezanilla
bioRxiv
Cold Spring Harbor Laboratory, 1.1
05/23/2025
DOI: 10.1101/2025.05.22.655422
PMCID: PMC12139949
PMID: 40475520
url
https://doi.org/10.1101/2025.05.22.655422View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Voltage-gated sodium channels initiate action potentials and control electrical signaling throughout the animal kingdom. Fast inactivation is an essential auto-inhibitory mechanism and requisite component of sodium channel physiology. Recent structural and electrophysiological results are inconsistent with the canonical ball and chain model of fast inactivation thus necessitating an updated theoretical framework. Here, we use encoded fluorescence spectroscopy and high-resolution electrophysiology to capture key steps in the fast inactivation mechanism, from voltage-sensor activation to pore occlusion, an ultra-fast process which occurs in less than 2 milliseconds. Upon depolarization, activation of the domain IV voltage sensor initiates cytoplasmic DIII_DIV linker movement and quickly repositions the IFM motif into a hydrophobic pocket adjacent to the pore. This triggers a structural rearrangement of the pocket. The phenylalanine of the IFM motif contacts the pore-forming helices via a hydrophobic interaction with S6 of DIV and an aromatic/hydrophobic interaction with S6 of DIIII. These two interactions occur only after both S6 segments rotate, thus exposing the hydrophobic gate into the pore producing the fast inactivation. Based on the current results, we propose an alternative lock and key model to explain the molecular mechanism of fast inactivation.
 Biophysics

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