Extracellular K+ modulates the pore conformations of Cys-loop receptor anion channels

Potassium (K+) is an essential cation for life. Extracellular K+ is mainly sensed by membrane proteins that use K+ as their substrates. Yet, no membrane protein that is gated by extracellular K+ as a ligand and exhibits a distinct signal has been discovered in animals. Here, we report that a Cys-loop receptor, CG12344/DmAlka, expressed in the Drosophila nervous system, is selectively modulated by a physiological concentration of extracellular K+. Structural prediction, electrophysiology and phylogenetic analysis of DmAlka revealed the extracellular K+ binding site that mimics the hydrated chemical environment for K+, as observed in K+ channel pore. Furthermore, we found that K+ binding induces a previously unrecognized mode-switching mechanism, altering properties ranging from ligand sensitivity to ion selectivity. Notably, a human glycine receptor variant also exhibited similar mechanisms. Our study reveals a regulatory mechanism of Cys-loop receptors that directly links the extracellular K+ signaling to Cl− conductance in animals. Potassium ion (K+) is essential for cellular functions, yet no animal membrane receptor was known to bind extracellular K+ as a ligand. Here, the authors identify a Drosophila Cys-loop receptor that is gated by extracellular K+, with a distinct mode switching mechanism.