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bioRxiv · 10.1101/2025.06.15.658987

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

Shimomura, T.·saitoe, M.·Kubo, Y.·Suzuki, Y.
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Abstract

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.

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Shimomura, T., saitoe, M., Kubo, Y., Suzuki, Y.. 2025-06-17. Extracellular K+ modulates the pore conformations of Cys-loop receptor anion channels. https://doi.org/10.1101/2025.06.15.658987

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