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Structural and Functional Mechanisms Underlying Activation Gate Dynamics and IFM Motif Accessibility in Human Nav1.5
Rupam Biswas1, Ana Laura López-Serrano2, Apoorva Purohit3
1Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, USA.
Biorxiv : the Preprint Server for Biology
|July 9, 2025
Summary
Researchers revealed a new structure of voltage-gated sodium channel Nav1.5, uncovering a novel ion binding site that impacts fast inactivation. This finding challenges existing models and offers new therapeutic strategies for cardiac arrhythmias.
Area of Science:
- Structural Biology
- Molecular Physiology
- Cardiovascular Research
Background:
- Voltage-gated sodium channels (Nav) are crucial for cellular excitability.
- Dysregulation of Nav channels is implicated in various diseases, including cardiac arrhythmias.
- Targeting Nav channels therapeutically is hindered by incomplete understanding of their gating mechanisms.
Purpose of the Study:
- To elucidate the structural basis of Nav1.5 gating.
- To investigate the role of a novel Na+ binding site in channel function.
- To challenge and refine existing models of fast inactivation.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine the structure of human Nav1.5.
- Molecular dynamics (MD) simulations to analyze ion binding and channel dynamics.
- Electrophysiological recordings to assess functional consequences of ion binding.
Main Results:
- A cryo-EM structure of Nav1.5 in an intermediate open state was resolved.
- A novel Na+ binding site adjacent to the inactivation (IFM) motif was identified.
- Ion binding at this site was shown to modulate IFM motif docking and fast inactivation kinetics.
- Dynamic regulation of IFM accessibility was observed, contradicting the hinged-lid model.
Conclusions:
- The study provides a revised structural framework for Nav1.5 gating.
- A novel mechanism for regulating fast inactivation via an adjacent ion binding site is proposed.
- Findings may inform the development of improved therapeutic strategies for Nav1.5-related cardiac conditions.
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