Orthosteric- versus allosteric-dependent activation of the GABAA receptor requires numerically distinct subunit level rearrangements

Abstract Anaesthetic molecules act on synaptic transmission via the allosteric modulation of ligand-gated chloride channels, such as hetero-oligomeric α1β2γ2 GABAA receptors. To elucidate the overall activation paradigm via allosteric versus orthosteric sites, we used highly homologous, but homo-oli...

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Autores principales:	Jahanshah Amin, Meena S. Subbarayan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c1db31aa7b9640a6b828479b3465e029
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spelling	oai:doaj.org-article:c1db31aa7b9640a6b828479b3465e0292021-12-02T15:05:36ZOrthosteric- versus allosteric-dependent activation of the GABAA receptor requires numerically distinct subunit level rearrangements10.1038/s41598-017-08031-92045-2322https://doaj.org/article/c1db31aa7b9640a6b828479b3465e0292017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08031-9https://doaj.org/toc/2045-2322Abstract Anaesthetic molecules act on synaptic transmission via the allosteric modulation of ligand-gated chloride channels, such as hetero-oligomeric α1β2γ2 GABAA receptors. To elucidate the overall activation paradigm via allosteric versus orthosteric sites, we used highly homologous, but homo-oligomeric, ρ1 receptors that are contrastingly insensitive to anaesthetics and respond partially to several full GABA α1β2γ2 receptor agonists. Here, we coexpressed varying ratios of RNAs encoding the wild-type and the mutated ρ1 subunits, which are anaesthetic-sensitive and respond with full efficacy to partial GABA agonists, to generate distinct ensembles of receptors containing five, four, three, two, one, or zero mutated subunits. Using these experiments, we then demonstrate that, in the pentamer, three anaesthetic-sensitive ρ1 subunits are needed to impart full efficacy to the partial GABA agonists. By contrast, five anaesthetic-sensitive subunits are required for direct activation by anaesthetics alone, and only one anaesthetic-sensitive subunit is sufficient to confer the anaesthetic-dependent potentiation to the GABA current. In conclusion, our data indicate that GABA and anaesthetics holistically activate the GABAA ρ1 receptor through distinct subunit level rearrangements and suggest that in contrast to the global impact of GABA via orthosteric sites, the force of anaesthetics through allosteric sites may not propagate to the neighbouring subunits and, thus, may have only a local and limited effect on the ρ1 GABAA receptor model system.Jahanshah AminMeena S. SubbarayanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jahanshah Amin Meena S. Subbarayan Orthosteric- versus allosteric-dependent activation of the GABAA receptor requires numerically distinct subunit level rearrangements
description	Abstract Anaesthetic molecules act on synaptic transmission via the allosteric modulation of ligand-gated chloride channels, such as hetero-oligomeric α1β2γ2 GABAA receptors. To elucidate the overall activation paradigm via allosteric versus orthosteric sites, we used highly homologous, but homo-oligomeric, ρ1 receptors that are contrastingly insensitive to anaesthetics and respond partially to several full GABA α1β2γ2 receptor agonists. Here, we coexpressed varying ratios of RNAs encoding the wild-type and the mutated ρ1 subunits, which are anaesthetic-sensitive and respond with full efficacy to partial GABA agonists, to generate distinct ensembles of receptors containing five, four, three, two, one, or zero mutated subunits. Using these experiments, we then demonstrate that, in the pentamer, three anaesthetic-sensitive ρ1 subunits are needed to impart full efficacy to the partial GABA agonists. By contrast, five anaesthetic-sensitive subunits are required for direct activation by anaesthetics alone, and only one anaesthetic-sensitive subunit is sufficient to confer the anaesthetic-dependent potentiation to the GABA current. In conclusion, our data indicate that GABA and anaesthetics holistically activate the GABAA ρ1 receptor through distinct subunit level rearrangements and suggest that in contrast to the global impact of GABA via orthosteric sites, the force of anaesthetics through allosteric sites may not propagate to the neighbouring subunits and, thus, may have only a local and limited effect on the ρ1 GABAA receptor model system.
format	article
author	Jahanshah Amin Meena S. Subbarayan
author_facet	Jahanshah Amin Meena S. Subbarayan
author_sort	Jahanshah Amin
title	Orthosteric- versus allosteric-dependent activation of the GABAA receptor requires numerically distinct subunit level rearrangements
title_short	Orthosteric- versus allosteric-dependent activation of the GABAA receptor requires numerically distinct subunit level rearrangements
title_full	Orthosteric- versus allosteric-dependent activation of the GABAA receptor requires numerically distinct subunit level rearrangements
title_fullStr	Orthosteric- versus allosteric-dependent activation of the GABAA receptor requires numerically distinct subunit level rearrangements
title_full_unstemmed	Orthosteric- versus allosteric-dependent activation of the GABAA receptor requires numerically distinct subunit level rearrangements
title_sort	orthosteric- versus allosteric-dependent activation of the gabaa receptor requires numerically distinct subunit level rearrangements
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c1db31aa7b9640a6b828479b3465e029
work_keys_str_mv	AT jahanshahamin orthostericversusallostericdependentactivationofthegabaareceptorrequiresnumericallydistinctsubunitlevelrearrangements AT meenassubbarayan orthostericversusallostericdependentactivationofthegabaareceptorrequiresnumericallydistinctsubunitlevelrearrangements
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Orthosteric- versus allosteric-dependent activation of the GABAA receptor requires numerically distinct subunit level rearrangements

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