Differential assembly diversifies GABA A receptor structures and signalling

Type A γ-aminobutyric acid receptors (GABA Rs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits and can be modulated by essential medicines including general anaesthetics and benzodiazepines . Human GABA R subunits are encoded by 19 paralogous...

Full description

Saved in:
Bibliographic Details
Published in:Nature (London) 2022-04, Vol.604 (7904), p.190
Main Authors: Sente, Andrija, Desai, Rooma, Naydenova, Katerina, Malinauskas, Tomas, Jounaidi, Youssef, Miehling, Jonas, Zhou, Xiaojuan, Masiulis, Simonas, Hardwick, Steven W, Chirgadze, Dimitri Y, Miller, Keith W, Aricescu, A Radu
Format: Article
Language:English
Subjects:
Benzodiazepines - pharmacology
Binding Sites
Cryoelectron Microscopy
gamma-Aminobutyric Acid - metabolism
Histamine - metabolism
Humans
Ligands
Protein Subunits - chemistry
Protein Subunits - metabolism
Receptors, GABA-A - chemistry
Receptors, GABA-A - metabolism
Receptors, GABA-A - ultrastructure
RNA-Seq
Signal Transduction
Single-Cell Analysis
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Type A γ-aminobutyric acid receptors (GABA Rs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits and can be modulated by essential medicines including general anaesthetics and benzodiazepines . Human GABA R subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. However, the principles that govern the formation of pentamers, the permutational landscape of receptors that may emerge from a subunit set and the effect that this has on GABAergic signalling remain largely unknown. Here we use cryogenic electron microscopy to determine the structures of extrasynaptic GABA Rs assembled from α4, β3 and δ subunits, and their counterparts incorporating γ2 instead of δ subunits. In each case, we identified two receptor subtypes with distinct stoichiometries and arrangements, all four differing from those previously observed for synaptic, α1-containing receptors . This, in turn, affects receptor responses to physiological and synthetic modulators by creating or eliminating ligand-binding sites at subunit interfaces. We provide structural and functional evidence that selected GABA R arrangements can act as coincidence detectors, simultaneously responding to two neurotransmitters: GABA and histamine. Using assembly simulations and single-cell RNA sequencing data , we calculated the upper bounds for receptor diversity in recombinant systems and in vivo. We propose that differential assembly is a pervasive mechanism for regulating the physiology and pharmacology of GABA Rs.
ISSN:1476-4687
DOI:10.1038/s41586-022-04517-3