Plausible model for voltage sensor modification by local anesthetics. Upon depolarization, the voltage sensors move outward and the pore of the sodium channel opens. For clarity, only domains I and III are shown. Lidocaine binds to the open pore with high affinity (open lidocaine bound). When the membrane is repolarized, the domain III pore helices are unable to close because of lidocaine occupying the binding site and destabilizing the resting state of the domain III voltage sensor relative to the open state. Strong hyperpolarization drives the domain III voltage sensor to a resting-like conformation, even though the lidocaine-binding site is occupied.