Extended Data Fig. 1: Kv4-specific gating mechanism.

Comparison of the inactivation mechanisms between Kv4 and Kv1. R: resting state; C: closed activated state; O: open activated state; OSI: open inactivated state (open state inactivation); CSI: closed inactivated state (closed state inactivation). Upon depolarization, Kv4 adopts CSI to become inactivated. CSI involves the closure of the S6 gate. OSI plays a minor role in Kv4 inactivation, although it is the main pathway to become inactivated in Kv1. Upon repolarization, Kv4 returns to the resting state (R) from CSI with the milliseconds order of the fast recovery rate whereas Kv1 returns to the resting state from OSI with the tens of seconds of the slow recovery rate. For a detailed schematic explanation, please see (b) below. a. Gating model of Kv4 without auxiliary subunits. Upon depolarization, the S4 (green) adopts the “up” conformation (closed activated: C), and then the S6 gate opens via the interaction with the S4-S5 linker (orange) to form the open activated conformation (O). After activation, Kv4 takes two distinct inactivation pathways. Open activated Kv4 (O) goes to an open inactivated state (OSI) through the occlusion of the pore by its own N-terminus (N-ball), which is characterized by fast inactivation kinetics and called N-type inactivation or open state inactivation (OSI). However, the open inactivated state of Kv4 (OSI) is not stable, and Kv4 reverts to a closed activated state (C) and then goes to a closed inactivated state (CSI). This process is characterized by slower inactivation kinetics than OSI and referred to as closed state inactivation (CSI) through the S6 closing and S4 conformational change. It should be noted that CSI is still a fast millisecond-order process. As a result, during depolarization Kv4 accumulates in a closed inactivated state (CSI). Upon repolarization, Kv4 recovers from CSI to the resting state (R) through the sliding down of S4 and the conformational change of S6.