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

K + is an essential cation for life, but no eukaryotic membrane protein with a modulatory site for extracellular K + has been discovered. Here, we report that a Cys-loop receptor, CG12344/DmAlka, expressed in the Drosophila nervous system, is selectively modulated by 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,” altering properties ranging from ligand sensitivity to ion selectivity. Notably, a human glycine receptor variant also exhibited similar mechanisms. Our study reveals a novel regulatory mechanism of Cys-loop receptors that directly links the extracellular K + signaling to Cl - conductance in animals.