Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway

Adrien H Cerdan (1, 2) , Laurie Peverini (2) , Jean-Pierre Changeux (2, 3, 4) , Pierre-Jean Corringer (2) , Marco Cecchini (1)

1 Institut de Chimie de Strasbourg
2 Récepteurs Canaux - Channel Receptors
3 Kavli Institute for Brain and Mind [San Diego]
4 CdF (institution) - Collège de France

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.

Domains: Biochemistry, Molecular Biology

Adrien H 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, 8 (41), pp.eadc9340. ⟨10.1126/sciadv.adc9340⟩. ⟨pasteur-03871918⟩