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Significance Hysteresis in hyperpolarization-gated ion channels determines a normal heartbeat, a stable rhythmic firing of pacemaking neurons, and synaptic integration. Hysteresis in ion-selectivity changes of the two-pore K+ channels regulates dynamically cell excitability, and recently it was shown that Kv7-channel's hysteretic gating mediates the Retigabine (an anticonvulsant)-dependent reduction of neuronal excitability. Given the ever-growing significance of this process in human physiology, it is imperative to determine its underlying structural bases. In this work, we have identified the molecular determinants of a hysteretic behavior in the prototypical ion channel, KcsA. Our results indicate that hysteresis or molecular “memory” in tetrameric cation-selective channels can arise from an allosteric coupling between the channel's activation gate and selectivity filter.

Hysteresis of KcsA potassium channel's activation– deactivation gating is caused by structural changes at the channel’s selectivity filter