A mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels

Yichen Liu, Carlos A. Z. Bassetto, Bernardo I. Pinto and Francisco Bezanilla ()
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Yichen Liu: University of Chicago
Carlos A. Z. Bassetto: University of Chicago
Bernardo I. Pinto: University of Chicago
Francisco Bezanilla: University of Chicago

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The hinged-lid model was long accepted as the canonical model for fast inactivation in Nav channels. It predicts that the hydrophobic IFM motif acts intracellularly as the gating particle that binds and occludes the pore during fast inactivation. However, the observation in recent high-resolution structures that the bound IFM motif is located far from the pore, contradicts this preconception. Here, we provide a mechanistic reinterpretation of fast inactivation based on structural analysis and ionic/gating current measurements. We demonstrate that in Nav1.4 the final inactivation gate is comprised of two hydrophobic rings at the bottom of S6 helices. These rings function in series and close downstream of IFM binding. Reducing the volume of the sidechain in both rings leads to a partially conductive, leaky inactivated state and decreases the selectivity for Na+ ion. Altogether, we present an alternative molecular framework to describe fast inactivation.

Date: 2023
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DOI: 10.1038/s41467-023-40514-4

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