eprintid: 10143776
rev_number: 8
eprint_status: archive
userid: 699
dir: disk0/10/14/37/76
datestamp: 2022-02-17 15:30:20
lastmod: 2022-02-17 15:30:30
status_changed: 2022-02-17 15:30:20
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Kasaragod, Vikram Babu
creators_name: Mortensen, Martin
creators_name: Hardwick, Steven W
creators_name: Wahid, Ayla A
creators_name: Dorovykh, Valentina
creators_name: Chirgadze, Dimitri Y
creators_name: Smart, Trevor G
creators_name: Miller, Paul S
title: Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors
ispublished: inpress
divisions: C08
divisions: G02
divisions: B02
divisions: UCL
divisions: D09
keywords: Cryoelectron microscopy, Ion channels in the nervous system, Molecular neuroscience
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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: 2022-02-09
date_type: published
publisher: Springer Science and Business Media LLC
official_url: https://doi.org/10.1038/s41586-022-04402-z
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1939476
doi: 10.1038/s41586-022-04402-z
lyricists_name: Smart, Trevor
lyricists_name: Mortensen, Martin
lyricists_id: TSMAR12
lyricists_id: MMORT55
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Nature
citation:        Kasaragod, Vikram Babu;    Mortensen, Martin;    Hardwick, Steven W;    Wahid, Ayla A;    Dorovykh, Valentina;    Chirgadze, Dimitri Y;    Smart, Trevor G;           Kasaragod, Vikram Babu;  Mortensen, Martin;  Hardwick, Steven W;  Wahid, Ayla A;  Dorovykh, Valentina;  Chirgadze, Dimitri Y;  Smart, Trevor G;  Miller, Paul S;   - view fewer <#>    (2022)    Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors.                   Nature        10.1038/s41586-022-04402-z <https://doi.org/10.1038/s41586-022-04402-z>.    (In press).    Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10143776/1/s41586-022-04402-z.pdf