Sensing the Electrochemical K+ Gradient: The Voltage Gating Mechanism in K2P Potassium Channels

Abstract

Two-pore domain (K2P) K+ channels represent a large family of ion channels that are major regulators of cellular excitability in the body and involved in a wide range of cellular mechanisms including apoptosis, vasodilatation, anaesthesia, pain, neuroprotection and temperature sensing. Many K2P channels are strongly activated by membrane depolarization, but the mechanisms underlying this voltage-dependent behaviour are unknown. Here we report that many K2P channels (e.g. TREK-1, TREK-2, TRAAK, TASK-3, TALK-2 and TRESK) are equipped with a gating machinery which directly senses the electrochemical K+ gradient and which gates the pore open when the membrane potential is positive to the K+ reversal potential. These properties couple voltage activation in K2P channels tightly to the reversal potential in distinction to classical Kv channels. We show that this sensing mechanism is located in the selectivity filter (SF), is strongly affected by the permeant ion species and operates as a check valve that is opened by outward permeation but closed by inward permeation. This gating behaviour is steeply voltage-dependent suggesting that multiple ions within the SF are moved simultaneously by the electrical field to gate the filter open. These findings highlight a mechanism of voltage-dependent gating which bypasses the need for electromechanical coupling to a separate voltage sensing module and is instead powered directly by the electrochemical gradient. This also further closes the mechanistic gap between ion channels and transporters because in both cases the electrochemical gradient is used to power a conformational change leading to either an ion translocation step in the case of a transporter or a pore gating step in K2P channels.