Asymmetric gating of a human hetero-pentameric glycine receptor

• Published in: Nature communications Vol. 14; no. 1; p. 6377
• Main Authors: Liu, Xiaofen, Wang, Weiwei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/1647/1453; 631/378/2586; 631/45/269/1149; 631/535/1258/1259; 64; 82/16; 82/29; 82/80; 82/83; 9/10; 96/106; 96/109; Amino acids; Asymmetry; Binding; Central nervous system; Channel gating; Cysteine Loop Ligand-Gated Ion Channel Receptors - chemistry; Cysteine Loop Ligand-Gated Ion Channel Receptors - metabolism; Glycine; Humanities and Social Sciences; Humans; Ion Channel Gating - physiology; multidisciplinary; Nervous system; Neurotransmission; Neurotransmitter receptors; Neurotransmitters; Receptors; Receptors, Glycine - metabolism; Science; Science (multidisciplinary); Signal processing; Signal transmission; Synaptic Transmission
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42051-6

Hetero-pentameric Cys-loop receptors constitute a major type of neurotransmitter receptors that enable signal transmission and processing in the nervous system. Despite intense investigations into their working mechanism and pharmaceutical potentials, how neurotransmitters activate these receptors remains unclear due to the lack of high-resolution structural information in the activated open state. Here we report near-atomic resolution structures resolved in digitonin consistent with all principle functional states of the human α1β GlyR, which is a major Cys-loop receptor that mediates inhibitory neurotransmission in the central nervous system of adults. Glycine binding induces cooperative and symmetric structural rearrangements in the neurotransmitter-binding extracellular domain but asymmetrical pore dilation in the transmembrane domain. Symmetric response in the extracellular domain is consistent with electrophysiological data showing cooperative glycine activation and contribution from both α1 and β subunits. A set of functionally essential but differentially charged amino acid residues in the transmembrane domain of the α1 and β subunits explains asymmetric activation. These findings provide a foundation for understanding how the gating of the Cys-loop receptor family members diverges to accommodate specific physiological environments. Despite essential roles in adult nervous systems, how heteromeric Cys-loop receptors work is unclear in the absence of an open state structure. Here, the authors report closed/open state structures and functional experiments, detailing an asymmetric gating mechanism driven by differing contributions from each subunit type.