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Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors.

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cam.depositDate2022-01-05
cam.issuedOnline2022-02-09
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cam.orpheus.successThu Feb 24 18:06:36 GMT 2022 - Embargo updated*
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dc.contributor.authorKasaragod, Vikram Babu
dc.contributor.authorMortensen, Martin
dc.contributor.authorHardwick, Steven
dc.contributor.authorWahid, Ayla
dc.contributor.authorDorovykh, Valentina
dc.contributor.authorChirgadze, Dima
dc.contributor.authorSmart, Trevor G
dc.contributor.authorMiller, Paul
dc.contributor.orcidMortensen, Martin [0000-0002-5873-7107]
dc.contributor.orcidHardwick, Steven [0000-0001-9246-1864]
dc.contributor.orcidWahid, Ayla [0000-0001-8128-9632]
dc.contributor.orcidChirgadze, Dima [0000-0001-9942-0993]
dc.contributor.orcidSmart, Trevor G [0000-0002-9089-5375]
dc.contributor.orcidMiller, Paul [0000-0002-6512-9441]
dc.date.accessioned2022-01-11T00:30:14Z
dc.date.available2022-01-11T00:30:14Z
dc.date.issued2022-02-09
dc.date.updated2022-01-05T09:03:37Z
dc.description.abstractType 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.
dc.description.sponsorshipThis work was supported by a Department of Pharmacology new lab start-up fund, the University of Cambridge Isaac Newton & Wellcome Trust Institutional Strategic Support Fund, and Academy of Medical Sciences Springboard Award (SBF004\1074). Electrophysiology work in the laboratory of Professor Trevor Smart was funded by an MRC programme grant (MR/T002581/1) and Wellcome Trust Collaborative Award (217199/Z/19/Z). The cryo-EM facility receives funding from the Wellcome Trust (206171/Z/17/Z; 202905/Z/16/Z) and University of Cambridge.
dc.identifier.doi10.17863/CAM.79757
dc.identifier.eissn1476-4687
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332581
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.departmentDepartment of Pharmacology
dc.rightsAttribution 4.0 International (CC BY)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleMechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors.
dc.typeArticle
dcterms.dateAccepted2021-12-22
prism.publicationNameNature
pubs.funder-project-idAcademy of Medical Sciences (SBF004\1074)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41586-022-04402-z

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