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Cited by 316Neuroscience and Neuropharmacology ResearchNicotinic Acetylcholine Receptors StudyReceptor Mechanisms and Signaling

Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer

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Laverty, Duncan, Desai, Rooma, Uchański, Tomasz, Masiulis, Simonas, Stec, Wojciech J., Malinauskas, Tomas, Zivanov, Jasenko, Pardon, Els +3 more·2019·Nature
DOI 10.1038/s41586-018-0833-4PMC PMC6364807
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Abstract

Type A γ-aminobutyric acid (GABA A) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system 1,2. Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia 3,4. Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the α1β2/3γ2 GABA A receptors 5. The β3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in β1-β3 triple knockout neurons 6. So far, efforts to generate accurate structural models for heteromeric GABA A receptors have been hampered by the use of engineered receptors and the presence of detergents 7-9. Notably, some recent cryo-electron microscopy reconstructions have reported 'collapsed' conformations 8,9; however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor 10,11, the large body of structural work on homologous homopentameric receptor variants 12 and the logic of an ion-channel architecture. Here we present a high-resolution cryo-electron microscopy structure of the full-length human α1β3γ2L-a major synaptic GABA A receptor isoform-that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator 'megabody' and is in a desensitized conformation. Each GABA A receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of α1 subunits. Beyond this level, the intracellular M3-M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABA A receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology.

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  • The GABAA receptor is a pentamer with two PI(4,5)P2 molecules constitutively associated; the PI(4,5)P2 headgroup occupies a positively charged pocket in the intracellular juxta-membrane region, and PI(4,5)P2 does not regulate channel function.

    “The GABAA receptor is a pentamer and two molecules of PI(4,5)P2 are constitutively associated with the receptor. The negatively charged headgroup of PI(4,5)P2 occupies a positively charged pocket in the intracellular juxta-membrane region of one of the subunits. The function of PI(4,5)P2 is not to regulate channel function.”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [118]

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Authors
Laverty, D., Desai, R., Uchański, T., Masiulis, S., Stec, W. J., Malinauskas, T., Zivanov, J., Pardon, E., Steyaert, J., Miller, K. W., & Aricescu, A. R.
Affiliations
  • MRC Laboratory of Molecular Biology (GB)
  • Harvard University (US)
  • Vrije Universiteit Brussel (BE)
  • Centre for Human Genetics (GB)
Corresponding author
  • Laverty, Duncan
  • Miller, Keith W.
  • Aricescu, A. Radu
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-01-02
Volume
565
Issue
7740
Pages
516-520
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-018-0833-4
PMC
PMC6364807
OpenAlex
W2906072858
Cited by
316
References
3
Citations by year
2026: 28 · 2025: 27 · 2024: 32 · 2023: 29 · 2022: 49 · 2021: 47 · 2020: 55 · 2019: 44 · 2018: 3
FWCI
17.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Cancer Research UK (A14414)
  • Research Councils UK
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (168735)
  • Medical Research Council (MR/L009609/1)
  • Biotechnology and Biological Sciences Research Council (BB/M024709/1)
  • National Institute of General Medical Sciences (P01GM058448)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
GABAA receptor, ligand-gated ion channels, lipid nanodiscs, receptor structure, positive allosteric modulators, phosphatidylinositol 4,5-bisphosphate, juxtamembrane region, heteromeric receptor assembly, GABAergic neurotransmission, inhibitory neurotransmission
MeSH terms
Allosteric Regulation, Amino Acid Sequence, Binding Sites, Electric Conductivity, Humans, Lipid Bilayers, Models, Molecular, Receptors, GABA-A, Phosphatidylinositol 4,5-Diphosphate, Protein Isoforms, Cryoelectron Microscopy, Protein Structure, Quaternary, Nanostructures, Molecular Docking Simulation

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