The IFM team in collaboration with researchers at Institut Pasteur found that ions travel through lateral fenestrations in the extracellular domain of synaptic receptors to cross the post-synaptic membrane. This discovery contradicts the conventional textbook model of ion permeation at chemical synapses and explain current rectification in anomalous mutants. These results have just appeared in Science Advances (IF 14.1).
Glycine receptors (GlyRs) are ligand-gated ion channels that mediate 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 GlyR-α1 with mutagenesis and single-channel electrophysiology and 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 in synaptic neurotransmission.
Adrien Cerdan, Laurie Peverini, Jean-Pierre Changeux, Pierre-Jean Corringer & Marco Cecchini
Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway
Science Advances 2022 DOI: 10.1126/sciadv.adc9340
Marco Cecchini, équipe IFM, Institut de Chimie (UMR 7177).
