Voltage-gated sodium (Nav) channels enable the rapid influx of sodium ions that are essential to generating the rising phase of the action potential. As originally described by Hodgkin and Huxley, once the Nav channel is activated, it switches to an inactivated state within milliseconds, a process they called inactivation. Internal perfusion of the giant axon of the squid with proteolytic enzymes eliminated inactivation, implying that the inactivation gate is an internal protein structure of the Nav channel. This result, together with the charge immobilization of the gating currents, led to the ball and chain model of inactivation. Deletion of the linker between domains III and IV of the four homologous domains of the Nav channel was found to remove fast inactivation. These observations evolved the ball and chain model to the hinged-lid model of fast inactivation, which dominated the field for nearly 30 years. Surprisingly, the structures of the Nav channel, determined by cryo-EM, showed that the IFM was not at the site predicted by the hinged-lid model. Upending the Na channel field, biophysical and mutagenesis studies revealed that the binding of the IFM motif allosterically closes an inactivation gate at the internal entrance of the Nav conduction system. In this Review, we compile the historical and structural evolution of the fast inactivation process, from the first functional descriptions to current models based on structural data.
Y et al. (2026) studied this question.