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

Duncan Laverty (), Rooma Desai, Tomasz Uchański, Simonas Masiulis, Wojciech J. Stec, Tomas Malinauskas, Jasenko Zivanov, Els Pardon, Jan Steyaert, Keith W. Miller () and A. Radu Aricescu ()
Additional contact information
Duncan Laverty: Cambridge Biomedical Campus
Rooma Desai: Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School
Tomasz Uchański: Vrije Universiteit Brussel (VUB)
Simonas Masiulis: Cambridge Biomedical Campus
Wojciech J. Stec: Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School
Tomas Malinauskas: Wellcome Centre for Human Genetics, University of Oxford
Jasenko Zivanov: Cambridge Biomedical Campus
Els Pardon: Vrije Universiteit Brussel (VUB)
Jan Steyaert: Vrije Universiteit Brussel (VUB)
Keith W. Miller: Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School
A. Radu Aricescu: Cambridge Biomedical Campus

Nature, 2019, vol. 565, issue 7740, 516-520

Abstract: Abstract Type A γ-aminobutyric acid (GABAA) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system1,2. Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia3,4. Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the α1β2/3γ2 GABAA receptors5. 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 neurons6. So far, efforts to generate accurate structural models for heteromeric GABAA receptors have been hampered by the use of engineered receptors and the presence of detergents7–9. Notably, some recent cryo-electron microscopy reconstructions have reported ‘collapsed’ conformations8,9; however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor10,11, the large body of structural work on homologous homopentameric receptor variants12 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 GABAA 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 GABAA 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 GABAA receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-018-0833-4 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:565:y:2019:i:7740:d:10.1038_s41586-018-0833-4

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-018-0833-4

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().