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 note: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 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