A single main-chain hydrogen bond required to keep GABA A receptors closed

Cecilia M Borghese; Jason D Galpin; Samuel Eriksson Lidbrink; Yuxuan Zhuang; Netrang G Desai; Rebecca J Howard; Erik Lindahl; Christopher A Ahern; Marcel P Goldschen-Ohm

doi:10.1038/s41467-025-61447-0

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A single main-chain hydrogen bond required to keep GABA A receptors closed

Journal article

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Peer reviewed

A single main-chain hydrogen bond required to keep GABA A receptors closed

Cecilia M Borghese, Jason D Galpin, Samuel Eriksson Lidbrink, Yuxuan Zhuang, Netrang G Desai, Rebecca J Howard, Erik Lindahl, Christopher A Ahern and Marcel P Goldschen-Ohm

Nature communications, Vol.16(1), 6107

07/03/2025

DOI: 10.1038/s41467-025-61447-0

PMCID: PMC12222489

PMID: 40603861

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Abstract

GABAA receptors (GABAARs) are the primary inhibitory neurotransmitter receptors throughout the central nervous system. Genetic mutations causing their dysfunction are related to a broad spectrum of human disorders such as epilepsy, neurodevelopment and intellectual disability, autism spectrum disorder, schizophrenia, and depression. GABAARs are also important drug targets for anxiolytics, anticonvulsants, antidepressants, and anesthetics. Despite significant progress in understanding their three-dimensional structure, a critical gap remains in determining the molecular basis for channel gating. We recently identified mutations in the M2-M3 linkers that suggest linker flexibility has asymmetric subunit-specific correlations with channel opening. Here we use non-canonical amino acids (ncAAs) to investigate the role of main-chain H-hydrogen bonds (H-bonds) that may stabilize the M2-M3 linkers. We show that a single main-chain H-bond within the β2 subunit M2-M3 linker inhibits pore opening and is required to keep the unliganded channel closed. Furthermore, breaking this H-bond accounts for approximately one third of the energy used to open the channel during activation by GABA. In contrast, the analogous H-bond in the α1 subunit has no effect on gating. Our molecular simulations support the idea that channel opening involves the state-dependent breakage/disruption of a specific main-chain H-bond within the β2 subunit M2-M3 linker.

Mutation

Animals

gamma-Aminobutyric Acid - metabolism

HEK293 Cells

Humans

Hydrogen Bonding

Ion Channel Gating

Models, Molecular

Protein Subunits - chemistry

Protein Subunits - genetics

Protein Subunits - metabolism

Receptors, GABA-A - chemistry

Receptors, GABA-A - genetics

Receptors, GABA-A - metabolism

Details

Title: Subtitle: A single main-chain hydrogen bond required to keep GABA A receptors closed
Creators: Cecilia M Borghese - The University of Texas at Austin
Jason D Galpin - University of Iowa
Samuel Eriksson Lidbrink - Stockholm University
Yuxuan Zhuang - Stockholm University
Netrang G Desai - The University of Texas at Austin
Rebecca J Howard - Stockholm University
Erik Lindahl - Stockholm University
Christopher A Ahern - University of Iowa
Marcel P Goldschen-Ohm - The University of Texas at Austin
Resource Type: Journal article
Publication Details: Nature communications, Vol.16(1), 6107
DOI: 10.1038/s41467-025-61447-0
PMID: 40603861
PMCID: PMC12222489
NLM abbreviation: Nat Commun
eISSN: 2041-1723
Publisher: Nature
Grant note: R01GM148591 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) 2019-02433 / Vetenskapsrådet (Swedish Research Council) R35GM148239 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) 2021-05806 / Vetenskapsrådet (Swedish Research Council)
Language: English
Date published: 07/03/2025
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984843584102771

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