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, A. Radu Aricescu

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

175 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)516-520
Number of pages5
JournalNature
Volume565
Issue number7740
DOIs
Publication statusPublished - 24 Jan 2019
Externally publishedYes

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