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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...
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