Asymmetric gating of a human hetero-pentameric glycine receptor.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 10 2023
11 10 2023
Historique:
received:
16
12
2022
accepted:
28
09
2023
medline:
23
10
2023
pubmed:
12
10
2023
entrez:
11
10
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37821459
doi: 10.1038/s41467-023-42051-6
pii: 10.1038/s41467-023-42051-6
pmc: PMC10567788
doi:
Substances chimiques
Receptors, Glycine
0
Cysteine Loop Ligand-Gated Ion Channel Receptors
0
Glycine
TE7660XO1C
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6377Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. Springer Nature Limited.
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