TY - INPR PB - Springer Science and Business Media LLC JF - Nature TI - Mechanisms of inhibition and activation of extrasynaptic ?? GABAA receptors N1 - 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/. ID - discovery10143776 UR - https://doi.org/10.1038/s41586-022-04402-z Y1 - 2022/02/09/ AV - public A1 - Kasaragod, Vikram Babu A1 - Mortensen, Martin A1 - Hardwick, Steven W A1 - Wahid, Ayla A A1 - Dorovykh, Valentina A1 - Chirgadze, Dimitri Y A1 - Smart, Trevor G A1 - Miller, Paul S KW - Cryoelectron microscopy KW - Ion channels in the nervous system KW - Molecular neuroscience N2 - Type A GABA (?-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of ?-, ?-, ?-, ?-, ?-, ?-, ?- and ?-subunits1. ??, ?4??, ?6?? and ?5?? 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 ?1??, ?2?? and ?3?? receptor responses5,7?12. Here, to resolve these distinctive features, we determined structures of the predominantly extrasynaptic ?? GABAA receptor class. An inhibited state bound by both the lethal paralysing agent ?-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 ?? receptors that adapt them to a role in tonic signalling. ER -