Molecular arrangement and modulation of extrasynaptic αβδ GABAA receptors

Abstract γ-aminobutyric acid Type-A (GABA A ) αβδ receptors regulate neuronal excitability and contribute to sleep, mood and motor coordination. However, the molecular arrangements of these receptors and the basis of GABA activation and δ-selective drug modulation remain unclear. We solve cryo-EM structures of α4β3δ receptors in an α-β-α-β-δ arrangement that contains two GABA binding pockets. GABA binding supports a classical β-subunit tilt and an outward configuration of the β-subunit M2-M3 loops. However, the δ subunit M2-M3 loop is orientated inward and the 9’ activation gate in the pore is closed, consistent with the low efficacy for these receptors. Addition of a δ-selective positive allosteric modulator (PAM), DS2-Me, reveals binding to an α-δ pocket that causes the 9’ activation gate to open. In this work we provide key insights into the stoichiometry, arrangement and molecular modes of GABA activation and δ-selective modulation of these critical regulators of neuronal excitability.

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Publication Details

Journal
Nature Communications
Published
2026-08-18
DOI
https://doi.org/10.1038/s41467-026-76879-5
Primary Topic
Neuroscience and Neuropharmacology Research
Type
article
Field-Weighted Citation Impact
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article

Molecular arrangement and modulation of extrasynaptic αβδ GABAA receptors

Jan Steyaert, Els Pardon, Michael Reutlinger, Lisa Joedicke et al.
Nature Communications
Neuroscience and Neuropharmacology Research
article

Molecular arrangement and modulation of extrasynaptic αβδ GABAA receptors

Jan Steyaert, Els Pardon, Michael Reutlinger, Lisa Joedicke, Trevor G. Smart, Martin Mortensen, Wan-Na Chen, Maria‐Clemencia Hernandez, Paul S. Miller, Stephanie A. Nestorow, Daniel Bertrand, Giuseppe Cecere, Graham Ladds, Ayla A. Wahid, Thomas Clairfeuille, Caroline E. Wyatt, Gregoire Friz
article en

Abstract

Abstract γ-aminobutyric acid Type-A (GABA A ) αβδ receptors regulate neuronal excitability and contribute to sleep, mood and motor coordination. However, the molecular arrangements of these receptors and the basis of GABA activation and δ-selective drug modulation remain unclear. We solve cryo-EM structures of α4β3δ receptors in an α-β-α-β-δ arrangement that contains two GABA binding pockets. GABA binding supports a classical β-subunit tilt and an outward configuration of the β-subunit M2-M3 loops. However, the δ subunit M2-M3 loop is orientated inward and the 9’ activation gate in the pore is closed, consistent with the low efficacy for these receptors. Addition of a δ-selective positive allosteric modulator (PAM), DS2-Me, reveals binding to an α-δ pocket that causes the 9’ activation gate to open. In this work we provide key insights into the stoichiometry, arrangement and molecular modes of GABA activation and δ-selective modulation of these critical regulators of neuronal excitability.

Nature Communications
Roche (Switzerland) (CH), Vrije Universiteit Brussel (BE), University of Cambridge (GB), HiQScreen (Switzerland) (CH), VIB-VUB Center for Structural Biology (BE), University College London (GB)
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Neuroscience and Neuropharmacology Research
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