A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K ⁺ Channels

Summary

Two-pore domain (K2P) K ⁺ channels are major regulators of excitability that endow cells with an outwardly rectifying background “leak” conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way “check valve” within the filter because outward movement of K ⁺ induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings provide insight into the functional plasticity of a K ⁺-selective filter and also refine our understanding of K2P channels and the mechanisms by which ion channels can sense voltage.

Graphical Abstract

Highlights

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  Most K2P channels exhibit strong voltage gating and are not simple leak channels

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  Voltage sensing involves movement of K ⁺ into the electric field of an inactive filter

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  MD simulation of permeation reveals insight into the filter gating mechanism

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  Many physiological stimuli modulate this voltage-gating behavior

Abstract

K2P channels, which do not possess a canonical voltage-sensing domain, can be voltage gated by an ion check valve mechanism.