A Mechanistic Reinterpretation of Fast Inactivation in Voltage-Gated Na+ Channels

Abstract

The hinged-lid model is 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 locates 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.

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“…After opening, Na v channels inactivate [they have an inactivating gate ( Liu et al, 2023 )] and cannot be opened until the membrane potential is repolarized. While inactivated, neurons cannot fire another action potential, which is defined as the absolute refractory period.…”

“…Na v 1.6 is enriched in the node of Ranvier of myelinated excitatory neurons and plays an essential role in initiating and propagating the action potential by lowering the threshold voltage (Wagnon et al, 2016). After opening, Na v channels inactivate [they have an inactivating gate (Liu et al, 2023)] and cannot be opened until the membrane potential is repolarized. While inactivated, neurons cannot fire another action potential, which is defined as the absolute refractory period.…”