OSCR

Structural basis for activation and potentiation in a human α5β3 GABA<sub>A</sub> receptor.

Overview

Authors: John Cowgill1, Chen Fan2,3, Jan Steyaert4,5, Rebecca J. Howard1,2, Erik Lindahl1,2,6,7
ORCID iDs: John Cowgill, Chen Fan, Jan Steyaert, Rebecca J. Howard, Erik Lindahl
  1. Department of Biochemistry and Biophysics, SciLifeLab, Stockholm University,Solna, Sweden
  2. Department of Applied Physics, SciLifeLab, KTH Royal Institute of Technology,Solna, Sweden
  3. Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine,Shanghai, China
  4. VIB-VUB Center for Structural Biology, VIB,Brussels, Belgium
  5. Structural Biology Brussels, Vrije Universiteit Brussel,Brussels, Belgium
  6. Department of Physics, Chemistry and Biology, Linköping University,Linköping, Sweden
  7. Department of Chemistry, University of Illinois at Urbana-Champaign,Urbana, IL USA
Institutions: Stockholm University (Sweden); KTH Royal Institute of Technology (Sweden); Shanghai Jiao Tong University (China); VIB-VUB Center for Structural Biology (Belgium); Vrije Universiteit Brussel (Belgium); Linköping University (Sweden); University of Illinois Urbana-Champaign (United States)
Journal: Nature communications, volume 17, issue 1, article 5289
Dates: received 23 October 2025; accepted 28 May 2026; published online 15 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-74279-3 · PMID 42297817 · PMCID PMC13269941 · OpenAlex W4406924204
Open access: gold, a free copy (OpenAlex)
Preprint: doi:10.1101/2025.01.27.635004
Status: data only
Categories: histology / microscopy (modality), human (organism), cellular / molecular (subfield)
Methods: Statistics
Keywords: Cryoelectron microscopy, Ligand-gated ion channels, Permeation and transport
MeSH: Receptors, GABA-A*, Animals, Cryoelectron Microscopy, Etomidate, gamma-Aminobutyric Acid, HEK293 Cells, Hippocampus, Humans, Models, Molecular, Protein Subunits, Zinc (* major topic)
Topic: Neuroscience and Neuropharmacology Research (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: Knut and Alice Wallenberg Foundation (2023.0254); Vetenskapsrådet (2019-02433, 2021-05806); Stockholms Universitet (FV-5.1.2-0523-19)
Citations: cited by 2 papers (Europe PMC); 76 references in the paper

Abstract

Anesthetics and anticonvulsants act, in part, through diverse populations of type-A ɣ-aminobutyric acid receptors (GABAARs) formed from a pool of 19 subunits. In the hippocampus, α5 subunits primarily coassemble with β3 and, in some cases, γ2, generating numerous subtypes with differential functional and pharmacological properties critical in learning and memory. The stoichiometry, structure, and gating of these subpopulations are poorly understood. Here we show using cryogenic electron microscopy and electrophysiology that the human α5β3 GABAAR predominantly assembles with 2α:3β stoichiometry, though a minority population of 1α:4β indicates multiple assemblies are possible. In a resting-like state, a conserved activation gate and Zn2+-coordination at histidines on β3 block ion conduction. Upon GABA binding, global rearrangements release Zn2+ and open the activation gate in nearly all receptors. The activated receptor is unaffected upon binding the anesthetic etomidate or anticonvulsant topiramate, supporting a conformational selection mechanism of action. This work thus reveals the assembly, activation, and modulation of a GABAAR subtype critical to cognition, providing templates for structure-based drug discovery.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

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Data

Datasets cited

Data availability

All unique/stable reagents generated in this study are available from the corresponding author, Erik Lindahl, without restriction. Cryo-EM density maps have been deposited in the Electron Microscopy Data Bank under accession numbers EMD-51980 (https://www.ebi.ac.uk/emdb/EMD-51980) (resting-like in micelles), EMD-52312 (https://www.ebi.ac.uk/emdb/EMD-52312) (GABA-bound in micelles), EMD-52416 (GABA-bound in nanodiscs), EMD-52313 (https://www.ebi.ac.uk/emdb/EMD-52313) (GABA-bound in nanodiscs, 1:4 α:β), EMD-52314 (https://www.ebi.ac.uk/emdb/EMD-52314) (GABA-bound in nanodiscs, long incubation with GABA), EMD-52315 (https://www.ebi.ac.uk/emdb/EMD-52315) (etomidate- and GABA-bound in nanodiscs), EMD-54031 (https://www.ebi.ac.uk/emdb/EMD-54031) (topiramate- and GABA-bound in nanodiscs, long incubation with topiramate and GABA), EMD-54151 (https://www.ebi.ac.uk/emdb/EMD-54151) (GABA-bound in nanodiscs, long incubation with topiramate and GABA). Model coordinates have been deposited in the Protein Data Bank under accession numbers PDB 9HAA (https://doi.org/10.2210/pdb9HAA/pdb) (resting-like in micelles), 9HNQ (https://doi.org/10.2210/pdb9HNQ/pdb) (GABA-bound in micelles), 9HUM (https://doi.org/10.2210/pdb9HUM/pdb) (GABA-bound in nanodiscs), 9HNR (https://doi.org/10.2210/pdb9HNR/pdb) (GABA-bound in nanodiscs, 1:4 α:β), 9HNS (https://doi.org/10.2210/pdb9HNS/pdb) (GABA-bound in nanodiscs, long incubation with GABA), 9HNT (https://doi.org/10.2210/pdb9HNT/pdb) (etomidate- and GABA-bound in nanodiscs), 9RL5 (https://doi.org/10.2210/pdb9RL5/pdb) (topiramate- and GABA-bound in nanodiscs, long incubation with topiramate and GABA), 9RPB (https://doi.org/10.2210/pdb9RPB/pdb) (GABA-bound in nanodiscs, long incubation with topiramate and GABA). Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 3 keywords, 11 MeSH terms, 3 funders, 73 references.

Cite

This paper

Cowgill, J., Fan, C., Steyaert, J., Howard, R. J., & Lindahl, E. (2026). Structural basis for activation and potentiation in a human α5β3 GABA<sub>A</sub> receptor. Nature communications, 17(1), 5289. https://doi.org/10.1038/s41467-026-74279-3

BibTeX

@article{cowgill2026structural,
author = {Cowgill, John and Fan, Chen and Steyaert, Jan and Howard, Rebecca J. and Lindahl, Erik},
title = {{Structural basis for activation and potentiation in a human α5β3 GABA\<sub\>A\</sub\> receptor}},
journal = {Nature communications},
year = {2026},
month = jun,
volume = {17},
number = {1},
pages = {5289},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-74279-3},
url = {https://doi.org/10.1038/s41467-026-74279-3},
pmid = {42297817},
pmcid = {PMC13269941}
}

RIS

TY - JOUR
AU - Cowgill, John
AU - Fan, Chen
AU - Steyaert, Jan
AU - Howard, Rebecca J.
AU - Lindahl, Erik
TI - Structural basis for activation and potentiation in a human α5β3 GABA<sub>A</sub> receptor
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/06/15
VL - 17
IS - 1
SP - 5289
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-74279-3
UR - https://doi.org/10.1038/s41467-026-74279-3
LA - en
ER -

CSL-JSON

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