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Crotonic Acid Blocks the $\textit{Gloeobacter}$ Ligand-Gated Ion Channel (GLIC) via the Extracellular Domain.

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Alqazzaz, MA 
Price, KL 
Lummis, SCR 


Cys-loop receptors play important roles in signal transduction in multicellular organisms, but similar proteins exist in prokaryotes, the best studied of which is the Gloeobacter ligand-gated ion channel (GLIC). GLIC is activated by protons with 50% activation (pH50) at pH 5.5, and while a histidine residue in its pore-forming α-helix (M2) is known to be involved in gating, there is also evidence of a proton-sensitive region in the extracellular domain. However, this proton-sensitive region does not appear to be located in the region of GLIC equivalent to the agonist binding site in related proteins. Here we explore functional effects of a range of compounds that could bind to this site and show that some GABA analogues, the most potent of which is crotonic acid, inhibit GLIC function. Mutagenesis and docking studies suggest crotonic acid can bind to this region of the protein and, when bound, can allosterically inhibit GLIC function. These data therefore suggest that there is a transduction pathway from the orthosteric binding site to the pore in GLIC, as exists in related eukaryotic ligand-gated ion channels, and thus provide further evidence that this prokaryotic receptor is a good model for understanding this family of proteins.



$\textit{Gloeobacter}$, Cys-loop receptor, pore block, antagonist, M2

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American Chemical Society
Medical Research Council (MR/L021676/1)
SCRL would like to thank the MRC for funding. MAA is funded by a Yousef Jameel scholarship.