PUBLICATION
Mechanism of gating and partial agonist action in the glycine receptor
- Authors
- Yu, J., Zhu, H., Lape, R., Greiner, T., Du, J., Lü, W., Sivilotti, L., Gouaux, E.
- ID
- ZDB-PUB-210826-5
- Date
- 2021
- Source
- Cell 184: 957-968.e21 (Journal)
- Registered Authors
- Keywords
- SMA, cryo-EM, gating mechanism, glycine receptor, ligand-gated ion channels, partial agonists action
- MeSH Terms
-
- Imaging, Three-Dimensional
- Cell Line
- Binding Sites
- Ion Channel Gating*
- Humans
- Maleates/chemistry
- Receptors, Glycine/agonists*
- Receptors, Glycine/genetics
- Receptors, Glycine/metabolism*
- Receptors, Glycine/ultrastructure
- Styrene/chemistry
- Models, Molecular
- HEK293 Cells
- gamma-Aminobutyric Acid/metabolism
- Animals
- Mutant Proteins/chemistry
- Mutant Proteins/metabolism
- Protein Domains
- Zebrafish
- Neurotransmitter Agents/metabolism
- Cryoelectron Microscopy
- Mutation/genetics
- Glycine
- PubMed
- 33567265 Full text @ Cell
Citation
Yu, J., Zhu, H., Lape, R., Greiner, T., Du, J., Lü, W., Sivilotti, L., Gouaux, E. (2021) Mechanism of gating and partial agonist action in the glycine receptor. Cell. 184:957-968.e21.
Abstract
Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists, whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Here, we study the glycine receptor with the full agonist glycine and the partial agonists taurine and γ-amino butyric acid (GABA). We use electrophysiology to show how partial agonists populate agonist-bound, closed channel states and cryo-EM reconstructions to illuminate the structures of intermediate, pre-open states, providing insights into previously unseen conformational states along the receptor reaction pathway. We further correlate agonist-induced conformational changes to Po across members of the receptor family, providing a hypothetical mechanism for partial and full agonist action at Cys-loop receptors.
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Phenotype
Mutations / Transgenics
Human Disease / Model
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