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Structural determinants and regulation of spontaneous activity in GABAA receptors

Sexton, CA; Penzinger, R; Mortensen, M; Bright, DP; Smart, TG; (2021) Structural determinants and regulation of spontaneous activity in GABAA receptors. Nature Communications , 12 (1) , Article 5457. 10.1038/s41467-021-25633-0. Green open access

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Abstract

GABA_{A} receptors are vital for controlling neuronal excitability and can display significant levels of constitutive activity that contributes to tonic inhibition. However, the mechanisms underlying spontaneity are poorly understood. Here we demonstrate a strict requirement for β3 subunit incorporation into receptors for spontaneous gating, facilitated by α4, α6 and δ subunits. The crucial molecular determinant involves four amino acids (GKER) in the β3 subunit's extracellular domain, which interacts with adjacent receptor subunits to promote transition to activated, open channel conformations. Spontaneous activity is further regulated by β3 subunit phosphorylation and by allosteric modulators including neurosteroids and benzodiazepines. Promoting spontaneous activity reduced neuronal excitability, indicating that spontaneous currents will alter neural network activity. This study demonstrates how regional diversity in GABA_{A} receptor isoform, protein kinase activity, and neurosteroid levels, can impact on tonic inhibition through the modulation of spontaneous GABA_{A} receptor gating.

Type: Article
Title: Structural determinants and regulation of spontaneous activity in GABAA receptors
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-021-25633-0
Publisher version: https://doi.org/10.1038/s41467-021-25633-0
Language: English
Additional information: © 2021 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Ligand-gated ion channels, Neuroscience, Patch clamp, Single-channel recording
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10135602
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