A Non-Canonical Voltage Sensor Controls Gating in K2P K+ Channels

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 3-4 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 not only provide insight into the functional plasticity of a K+-selective filter, but also redefine our view of K2P channels and the mechanisms by which ion channels can sense voltage.