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Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway
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Edité par CCSD ; American Association for the Advancement of Science (AAAS) -
In-house VMD scripts for counting ion permeation events via the lateral/apical pathways over time and counting the number of chloride ions in the vestibule are provided at the following links: https://doi.org/10.5281/zenodo.6935496 and https://doi.org/10.5281/zenodo.6935478. Molecular snapshots of the zebrafish GlyR-α1 solvated and embedded in a lipid bilayer in the MD-open conformation that were used as starting points for the computational electrophysiology experiments are provided at the following link: https://doi.org/10.5281/zenodo.6529095. All other data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.. International audience. Glycine receptors (GlyR) are ligand-gated ion channels mediating signal transduction at chemical synapses. Since the early patch-clamp electrophysiology studies, the details of the ion permeation mechanism have remained elusive. Here, we combine molecular dynamics simulations of a zebrafish GlyR-⍺1 model devoid of the intracellular domain with mutagenesis and single-channel electrophysiology of the full-length human GlyR-⍺1. We show that lateral fenestrations between subunits in the extracellular domain provide the main translocation pathway for chloride ions to enter/exit a central water-filled vestibule at the entrance of the transmembrane channel. In addition, we provide evidence that these fenestrations are at the origin of current rectification in known anomalous mutants and design de novo two inward-rectifying channels by introducing mutations within them. These results demonstrate the central role of lateral fenestrations on synaptic neurotransmission. Teaser Extracellular chloride ions access the glycine receptor pore via lateral fenestrations outdating the standard apical model.
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