Slow inactivated states in voltage-gated ion channels can be modulated by binding molecules both to the outside and to the inside of the pore. Thus, external K+ inhibits C-type inactivation in Shaker K+ channels by a "foot-in-the-door" mechanism. Here, we explore the modulation of a very long-lived inactivated state, ultraslow inactivation (IUS), by ligand binding to the outer vestibule in voltage-gated Na+ channels. Blocking the outer vestibule by a mutant μ-conotoxin GIIIA substantially accelerated recovery from IUS. A similar effect was observed if Cd2+ was bound to a cysteine engineered to the selectivity filter (K1237C). In K1237C channels, exposed to 30 μM Cd 2+, the time constant of recovery from IUS was decreased from 145.0 ± 10.2 s to 32.5 ± 3.3 s (P < 0.001). Recovery from IUS was only accelerated if Cd2+ was added to the bath solution during recovery (V = -120 mV) from IUS, but not when the channels were selectively exposed to Cd2+ during the development of IUS (-20 mV). These data could be explained by a kinetic model in which Cd2+ binds with high affinity to a slow inactivated state (IS), which is transiently occupied during recovery from I US. A total of 50 μM Cd2+ produced an ∼8 mV hyperpolarizing shift of the steady-state inactivation curve of IS, supporting this kinetic model. Binding of lidocaine to the internal vestibule significantly reduced the number of channels entering IUS, suggesting that IUS is associated with a conformational change of the internal vestibule of the channel. We propose a molecular model in which slow inactivation (IS) occurs by a closure of the outer vestibule, whereas IUS arises from a constriction of the internal vestibule produced by a widening of the selectivity filter region. Binding of Cd2+ to C1237 promotes the closure of the selectivity filter region, thereby hastening recovery from IUS. Thus, Cd2+ ions may act like a foot-on-the-door, kicking the IS gate to close.