Panel A: A side view diagram of the sodium channel structure highlighting the position of hydrophobic gate residues in the pore (dark blue) and the IFM motif (red). Panel B: Two views of the sodium channel pore showing the extracellular and intracellular perspectives with labeled residues. A graph of pore radius along the pore length indicates the narrowing where hydrophobic residues reside. Panel C: Line graphs showing the effects of mutations on ionic currents. The graphs compare wild type (WT) and various mutations (I284A, I288A, DIIIAA) with labels indicating the leaky inactivated state for the double mutation.
Structural identification of the hydrophobic gate underlying fast inactivation. (A) View of the position of the hydrophobic gate residues in the pore of the sodium channel (in dark blue) and the location of the IFM motif (in red). Numbering is based on rNav1.4. (B) Pore radius along the length of the pore, indicating the narrowing where the two layers of hydrophobic residues reside. Residue numbers are named from rNav1.4 (modified from Liu et al., 2023). (C) Effects on ionic currents of mutations of the gate residues on ionic traces. For simplicity, only domain III is shown. Ionic currents families are shown for WT, the two DIII single alanine mutations (I284A and I288A), and the double alanine mutation, named DIIIAA. Only when both residues were mutated simultaneously was a steady-state current observed through the leaky inactivated state, as indicated by the cartoons next to the current traces (modified from Liu et al., 2023).