An atomic interaction conserved for over 600 million years gates inhibitory neurotransmission

Cecilia M Borghese; Netrang G Desai; Pranavi Garlapati; Syedah K Shah; Jason D Galpin; Luthary Segura; Nandan Haloi; Harold H Zakon; Rebecca J Howard; Erik Lindahl; Christopher A Ahern; Marcel P Goldschen-Ohm

doi:10.64898/2026.05.22.727206

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An atomic interaction conserved for over 600 million years gates inhibitory neurotransmission

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An atomic interaction conserved for over 600 million years gates inhibitory neurotransmission

Cecilia M Borghese, Netrang G Desai, Pranavi Garlapati, Syedah K Shah, Jason D Galpin, Luthary Segura, Nandan Haloi, Harold H Zakon, Rebecca J Howard, Erik Lindahl, …

bioRxiv

Cold Spring Harbor Laboratory

05/26/2026

DOI: 10.64898/2026.05.22.727206

PMCID: PMC13232294

PMID: 42244611

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https://doi.org/10.64898/2026.05.22.727206View

Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Pentameric ligand-gated ion channels (pLGICs) mediate fast inhibitory neurotransmission critical for neuronal network stability. A tyrosine residue in the M2-M3 linker of inhibitory pLGICs, conserved for over 600 million years, is positioned where it could hydrogen bond (H-bond) to the backbone of the neighboring Cys-loop. Given the pathogenic effects of variants of this tyrosine, we hypothesized that this H-bond stabilizes extracellular-to-transmembrane domain coupling essential for channel gating. To test this hypothesis, we used site-directed mutagenesis, noncanonical amino acid incorporation, and electrophysiological recordings in oocytes to disrupt this hydrogen bond in GABA and glycine receptors. Loss of this interaction via tyrosine substitutions or backbone amide modifications that ablate the acceptor or donor, respectively, markedly decrease agonist sensitivity and maximal channel activation, with effects localized to specific subunits. Molecular dynamics simulations support a role for this H-bond in channel gating. These findings reveal a critical atomic interaction underlying a shared mechanism for inhibitory receptor gating and provide a mechanistic explanation for disease-associated mutations linked to epilepsy, neurodevelopmental disability, and hyperekplexia.

Details

Title: Subtitle: An atomic interaction conserved for over 600 million years gates inhibitory neurotransmission
Creators: Cecilia M Borghese - The University of Texas at Austin
Netrang G Desai - The University of Texas at Austin
Pranavi Garlapati - The University of Texas at Austin
Syedah K Shah - The University of Texas at Austin
Jason D Galpin - University of Iowa
Luthary Segura - The University of Texas at Austin
Nandan Haloi - Stockholm University
Harold H Zakon - The University of Texas at Austin
Rebecca J Howard - Stockholm University
Erik Lindahl - Linköping University
Christopher A Ahern - University of Iowa
Marcel P Goldschen-Ohm - The University of Texas at Austin
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.64898/2026.05.22.727206
PMID: 42244611
PMCID: PMC13232294
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory; United States
Language: English
Date posted: 05/26/2026
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9985174709802771

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