A pore-facing glycan constrains GABAA receptor subunit stoichiometry and gating behavior
- 1Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi
Abstract
The gating and function of γ-aminobutyric acid type A receptors (GABAARs) depend on their hetero-pentameric subunit composition, yet the rules guiding subunit selection remain unclear. We show that a conserved N-linked glycan in α subunits, uniquely positioned within the extracellular pore, acts as a structural constraint that limits the functional viability of α-containing assemblies. A total of 32 µs of molecular dynamics simulations of native and hypothetical non-canonical assemblies show that adding a third pore-facing glycan or placing two glycans on adjacent subunits disrupts key interactions at the β+/α– interface containing the GABA-binding site. These perturbations propagate allosterically, alter extracellular–transmembrane domain coupling, and promote deep gate closure. Systems with three pore-facing glycans consistently adopt deep-closed conformations, whereas native assemblies with two glycans preserve interfacial integrity and pore hydration. These results identify the pore-facing glycan as a structural constraint on functionally viable GABAAR architecture and gating.
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BibTeX
@article{akbariahangar2026porefacing,
title = {{A pore-facing glycan constrains GABAA receptor subunit stoichiometry and gating behavior}},
author = {Amin Akbari-Ahangar and Jing Li},
journal = {Communications Biology},
year = {2026},
month = jul,
doi = {10.1038/s42003-026-10547-8},
url = {https://doi.org/10.1038/s42003-026-10547-8},
note = {CC BY},
}
RIS
TY - JOUR
TI - A pore-facing glycan constrains GABAA receptor subunit stoichiometry and gating behavior
AU - Amin Akbari-Ahangar
AU - Jing Li
PY - 2026
DA - 2026/07/01
JO - Communications Biology
DO - 10.1038/s42003-026-10547-8
UR - https://doi.org/10.1038/s42003-026-10547-8
AB - The gating and function of γ-aminobutyric acid type A receptors (GABAARs) depend on their hetero-pentameric subunit composition, yet the rules guiding subunit selection remain unclear. We show that a conserved N-linked glycan in α subunits, uniquely positioned within the extracellular pore, acts as a structural constraint that limits the functional viability of α-containing assemblies. A total of 32 µs of molecular dynamics simulations of native and hypothetical non-canonical assemblies show that adding a third pore-facing glycan or placing two glycans on adjacent subunits disrupts key interactions at the β+/α– interface containing the GABA-binding site. These perturbations propagate allosterically, alter extracellular–transmembrane domain coupling, and promote deep gate closure. Systems with three pore-facing glycans consistently adopt deep-closed conformations, whereas native assemblies with two glycans preserve interfacial integrity and pore hydration. These results identify the pore-facing glycan as a structural constraint on functionally viable GABAAR architecture and gating.
SN - 2399-3642
ER -