Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor

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Abstract

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-EM 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.

Data availability

The coordinates and volumes for the cryo-EM data have been deposited in the Electron Microscopy Data Bank under accession codes EMD-26316, EMD-26315, and EMD-26317. The coordinates have been deposited in the Protein Data Bank under accession codes 7U2N, 7U2M. and 7U2O.All data generated during this study is included in the manuscript and supporting files, Source data spreadsheets are provided for the electrophysiology data.

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Josip Ivica

Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Hongtao Zhu

Vollum Institute, Oregon Health and Science University Hospital, Portland, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1522-0500
Remigijus Lape

Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Eric Gouaux

Vollum Institute, Oregon Health and Science University Hospital, Portland, United States

For correspondence
gouauxe@ohsu.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8549-2360
Lucia G Sivilotti

Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

For correspondence
l.sivilotti@ucl.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7943-604X

Funding

Medical Research Council (Project grant MR/R009074/1)

Lucia G Sivilotti

National Institutes of Health (R01 GM100400)

Eric Gouaux

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.