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Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor
To clarify the determinants of agonist efficacy in pentameric ligand-gated ion channels, we examined a new compound, aminomethanesulfonic acid (AMS), a molecule intermediate in structure between glycine and taurine. Despite wide availability, to date there are no reports of AMS action on glycine rec...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462852/ https://www.ncbi.nlm.nih.gov/pubmed/35975975 http://dx.doi.org/10.7554/eLife.79148 |
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author | Ivica, Josip Zhu, Hongtao Lape, Remigijus Gouaux, Eric Sivilotti, Lucia G |
author_facet | Ivica, Josip Zhu, Hongtao Lape, Remigijus Gouaux, Eric Sivilotti, Lucia G |
author_sort | Ivica, Josip |
collection | PubMed |
description | To clarify the determinants of agonist efficacy in pentameric ligand-gated ion channels, we examined a new compound, aminomethanesulfonic acid (AMS), a molecule intermediate in structure between glycine and taurine. Despite wide availability, to date there are no reports of AMS action on glycine receptors, perhaps because AMS is unstable at physiological pH. Here, we show that at pH 5, AMS is an efficacious agonist, eliciting in zebrafish α1 glycine receptors a maximum single-channel open probability of 0.85, much greater than that of β-alanine (0.54) or taurine (0.12), and second only to that of glycine itself (0.96). Thermodynamic cycle analysis of the efficacy of these closely related agonists shows supra-additive interaction between changes in the length of the agonist molecule and the size of the anionic moiety. Single particle cryo-electron microscopy structures of AMS-bound glycine receptors show that the AMS-bound agonist pocket is as compact as with glycine, and three-dimensional classification demonstrates that the channel populates the open and the desensitized states, like glycine, but not the closed intermediate state associated with the weaker partial agonists, β-alanine and taurine. Because AMS is on the cusp between full and partial agonists, it provides a new tool to help us understand agonist action in the pentameric superfamily of ligand-gated ion channels. |
format | Online Article Text |
id | pubmed-9462852 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-94628522022-09-10 Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor Ivica, Josip Zhu, Hongtao Lape, Remigijus Gouaux, Eric Sivilotti, Lucia G eLife Structural Biology and Molecular Biophysics To clarify the determinants of agonist efficacy in pentameric ligand-gated ion channels, we examined a new compound, aminomethanesulfonic acid (AMS), a molecule intermediate in structure between glycine and taurine. Despite wide availability, to date there are no reports of AMS action on glycine receptors, perhaps because AMS is unstable at physiological pH. Here, we show that at pH 5, AMS is an efficacious agonist, eliciting in zebrafish α1 glycine receptors a maximum single-channel open probability of 0.85, much greater than that of β-alanine (0.54) or taurine (0.12), and second only to that of glycine itself (0.96). Thermodynamic cycle analysis of the efficacy of these closely related agonists shows supra-additive interaction between changes in the length of the agonist molecule and the size of the anionic moiety. Single particle cryo-electron microscopy structures of AMS-bound glycine receptors show that the AMS-bound agonist pocket is as compact as with glycine, and three-dimensional classification demonstrates that the channel populates the open and the desensitized states, like glycine, but not the closed intermediate state associated with the weaker partial agonists, β-alanine and taurine. Because AMS is on the cusp between full and partial agonists, it provides a new tool to help us understand agonist action in the pentameric superfamily of ligand-gated ion channels. eLife Sciences Publications, Ltd 2022-08-17 /pmc/articles/PMC9462852/ /pubmed/35975975 http://dx.doi.org/10.7554/eLife.79148 Text en © 2022, Ivica, Zhu et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Structural Biology and Molecular Biophysics Ivica, Josip Zhu, Hongtao Lape, Remigijus Gouaux, Eric Sivilotti, Lucia G Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor |
title | Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor |
title_full | Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor |
title_fullStr | Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor |
title_full_unstemmed | Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor |
title_short | Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor |
title_sort | aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor |
topic | Structural Biology and Molecular Biophysics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462852/ https://www.ncbi.nlm.nih.gov/pubmed/35975975 http://dx.doi.org/10.7554/eLife.79148 |
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