Journal article
Molecular basis of sodium channel inactivation
Nature communications, Vol.16(1), 10565
11/26/2025
DOI: 10.1038/s41467-025-65587-1
PMCID: PMC12658180
PMID: 41298396
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 DIII. 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.
Details
- Title: Subtitle
- Molecular basis of sodium channel inactivation
- Creators
- Yichen Liu - University of ChicagoJason D Galpin - University of IowaChristopher A Ahern - University of IowaFrancisco Bezanilla - Centro Interdisciplinario de Neurociencias de Valparaiso, Valparaiso, Chile. fbezanilla@uchicago.edu
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.16(1), 10565
- DOI
- 10.1038/s41467-025-65587-1
- PMID
- 41298396
- PMCID
- PMC12658180
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Springer Nature
- Grant note
- R35GM148239 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) QuBBE QLCI (NSF OMA-2121044) / National Science Foundation (NSF) R01-GM150272 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01-GM030376 / U.S. Department of Health & Human Services | National Institutes of Health (NIH)
- Language
- English
- Date published
- 11/26/2025
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9985034934002771
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