An Extracellular Ion Pathway Plays a Central Role in the Cooperative Gating of a K-2P K+ Channel by Extracellular pH

Abstract

Proton-gated TASK-3K(+) channel belongs to the K-2P family of proteins that underlie the K+ leak setting the membrane potential in all cells. TASK-3 is under cooperative gating control by extracellular [H+]. Use of recently solved K-2P structures allows us to explore the molecular mechanism of TASK-3 cooperative pH gating. Tunnel-like side portals define an extracellular ion pathway to the selectivity filter. We use a combination of molecular modeling and functional assays to show that pH-sensing histidine residues and K+ ions mutually interact electrostatically in the confines of the extracellular ion pathway. K+ ions modulate the pK(a) of sensing histidine side chains whose charge states in turn determine the open/closed transition of the channel pore. Cooperativity, and therefore steep dependence of TASK-3 K+ channel activity on extracellular pH, is dependent on an effect of the permeant ion on the channel pH(o) sensors.