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Structural determinants and regulation of spontaneous activity in GABA(A) receptors
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 incorporat...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443696/ https://www.ncbi.nlm.nih.gov/pubmed/34526505 http://dx.doi.org/10.1038/s41467-021-25633-0 |
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author | Sexton, Craig A. Penzinger, Reka Mortensen, Martin Bright, Damian P. Smart, Trevor G. |
author_facet | Sexton, Craig A. Penzinger, Reka Mortensen, Martin Bright, Damian P. Smart, Trevor G. |
author_sort | Sexton, Craig A. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8443696 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84436962021-10-04 Structural determinants and regulation of spontaneous activity in GABA(A) receptors Sexton, Craig A. Penzinger, Reka Mortensen, Martin Bright, Damian P. Smart, Trevor G. Nat Commun Article 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. Nature Publishing Group UK 2021-09-15 /pmc/articles/PMC8443696/ /pubmed/34526505 http://dx.doi.org/10.1038/s41467-021-25633-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access 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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Sexton, Craig A. Penzinger, Reka Mortensen, Martin Bright, Damian P. Smart, Trevor G. Structural determinants and regulation of spontaneous activity in GABA(A) receptors |
title | Structural determinants and regulation of spontaneous activity in GABA(A) receptors |
title_full | Structural determinants and regulation of spontaneous activity in GABA(A) receptors |
title_fullStr | Structural determinants and regulation of spontaneous activity in GABA(A) receptors |
title_full_unstemmed | Structural determinants and regulation of spontaneous activity in GABA(A) receptors |
title_short | Structural determinants and regulation of spontaneous activity in GABA(A) receptors |
title_sort | structural determinants and regulation of spontaneous activity in gaba(a) receptors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443696/ https://www.ncbi.nlm.nih.gov/pubmed/34526505 http://dx.doi.org/10.1038/s41467-021-25633-0 |
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