Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Ivica, Josip, Zhu, Hongtao, Lape, Remigijus, Gouaux, Eric, Sivilotti, Lucia G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
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
_version_ 1784787283320242176
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
work_keys_str_mv AT ivicajosip aminomethanesulfonicacidilluminatestheboundarybetweenfullandpartialagonistsofthepentamericglycinereceptor
AT zhuhongtao aminomethanesulfonicacidilluminatestheboundarybetweenfullandpartialagonistsofthepentamericglycinereceptor
AT laperemigijus aminomethanesulfonicacidilluminatestheboundarybetweenfullandpartialagonistsofthepentamericglycinereceptor
AT gouauxeric aminomethanesulfonicacidilluminatestheboundarybetweenfullandpartialagonistsofthepentamericglycinereceptor
AT sivilottiluciag aminomethanesulfonicacidilluminatestheboundarybetweenfullandpartialagonistsofthepentamericglycinereceptor