Sodium Channel Inactivation Goes with the Flow

Voltage-dependent inactivation of Na⁺ channels is a consequence of voltage-dependent activation (Aldrich et al., 1983), and inactivation is characterized by at least two distinguishable kinetic components: an initial rapid component (fast inactivation) and a slower component (slow inactivation). Within milliseconds of opening, Na⁺ channels enter a nonconducting inactivated state as the inactivation gate, the cytoplasmic loop linking domains III and IV of the α subunit, occludes the open pore (Stuhmer et al., 1989; Patton et al., 1992; West et al., 1992; McPhee et al., 1994, 1995, 1998; Kellenberger et al., 1996; Catterall, 2000). Residues that form a hydrophobic triplet (IFM) in the III-IV linker are crucial to fast inactivation (West et al., 1992), and the IFM motif has been suggested to function as a “latch” that holds the fast inactivation...