Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors
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Kasaragod, V., Mortensen, M., Hardwick, S., Wahid, A., Dorovyhk, V., Chirgadze, D., Smart, T., & et al. Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors. Nature https://doi.org/10.17863/CAM.79757
Extrasynaptic γ-aminobutyric acid (GABA) Type-A receptors, such as αβ, α4/6βδ and α5βγ receptors, mediate an essential persistent (tonic) inhibitory conductance in many regions of the mammalian brain 1,2. Human receptor mutations are linked to epilepsy and insomnia 3,4. Altered extrasynaptic receptor function is implicated in insomnia, stroke, Angelman, Fragile X, 1,5 and drugs against them treat postpartum depression 6. Tonic GABAergic responses are moderated to avoid over-suppressing neuronal communication, and can exhibit high sensitivity to Zn2+ blockade, which contrasts with synapse preferring α1/2/3βγ receptor responses 5,7-12. To resolve these distinctive features, we determined structures of the predominantly extrasynaptic receptor class. An inhibited state bound by the lethal paralysing agent α-cobratoxin (α-CBTx) 13 plus Zn2+, was used for comparison to 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 reaching the pore. Unusually, expansion of the midway pore activation gate is limited and it remains closed, reflecting the intrinsic low efficacy that characterises this receptor. Overall, this study explains distinct traits adopted by αβ receptors that adapt them to a role in tonic signalling.
This 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.
Academy of Medical Sciences (SBF004\1074)
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This record's DOI: https://doi.org/10.17863/CAM.79757
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332581
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