Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors

Vikram Babu Kasaragod, Martin Mortensen, Steven W. Hardwick, Ayla A. Wahid, Valentina Dorovykh, Dimitri Y. Chirgadze, Trevor G. Smart () and Paul S. Miller ()
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Vikram Babu Kasaragod: University of Cambridge
Martin Mortensen: University College London
Steven W. Hardwick: University of Cambridge
Ayla A. Wahid: University of Cambridge
Valentina Dorovykh: University College London
Dimitri Y. Chirgadze: University of Cambridge
Trevor G. Smart: University College London
Paul S. Miller: University of Cambridge

Nature, 2022, vol. 602, issue 7897, 529-533

Abstract: Abstract Type A GABA (γ-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of α-, β-, γ-, δ-, ε-, ρ-, θ- and π-subunits1. αβ, α4βδ, α6βδ and α5βγ receptors favour extrasynaptic localization, and mediate an essential persistent (tonic) inhibitory conductance in many regions of the mammalian brain1,2. Mutations of these receptors in humans are linked to epilepsy and insomnia3,4. Altered extrasynaptic receptor function is implicated in insomnia, stroke and Angelman and Fragile X syndromes1,5, and drugs targeting these receptors are used to treat postpartum depression6. Tonic GABAergic responses are moderated to avoid excessive suppression of neuronal communication, and can exhibit high sensitivity to Zn2+ blockade, in contrast to synapse-preferring α1βγ, α2βγ and α3βγ receptor responses5,7–12. Here, to resolve these distinctive features, we determined structures of the predominantly extrasynaptic αβ GABAA receptor class. An inhibited state bound by both the lethal paralysing agent α-cobratoxin13 and Zn2+ was used in comparisons with GABA–Zn2+ and GABA-bound structures. Zn2+ nullifies the GABA response by non-competitively plugging the extracellular end of the pore to block chloride conductance. In the absence of Zn2+, the GABA signalling response initially follows the canonical route until it reaches the pore. In contrast to synaptic GABAA receptors, expansion of the midway pore activation gate is limited and it remains closed, reflecting the intrinsic low efficacy that characterizes the extrasynaptic receptor. Overall, this study explains distinct traits adopted by αβ receptors that adapt them to a role in tonic signalling.

Date: 2022
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DOI: 10.1038/s41586-022-04402-z

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