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Control of cell surface expression of GABAA receptors by a conserved region at the end of the N-terminal extracellular domain of receptor subunits

Yuan, Banghao; Hatchett-Walker, Caroline; Long, Philip; Xu, Zhihan; Stephenson, F Anne; Haider, Shozeb; Jovanovic, Jasmina N; (2022) Control of cell surface expression of GABAA receptors by a conserved region at the end of the N-terminal extracellular domain of receptor subunits. Journal of Biological Chemistry , Article 102590. 10.1016/j.jbc.2022.102590. (In press). Green open access

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Abstract

Type A γ-aminobutyric acid receptors (GABAARs) represent a family of pentameric GABA-gated Cl-/HCO3- ion channels which mediate inhibitory transmission in the central nervous system (CNS). Cell surface expression of GABAARs, a prerequisite for their function, is dependent on the appropriate assembly of the receptor subunits and their transient interactions with molecular chaperones within the endoplasmic reticulum (ER) and Golgi apparatus. Here we describe a highly conserved amino acid sequence within the extracellular N-terminal domain of the receptor subunits adjoining the first transmembrane domain (TM1) as a region important for GABAAR processing within the ER. Modifications of this region in the α1, β3 and γ2 subunits using insertion or site-directed mutagenesis impaired GABAAR trafficking to the cell surface in heterologous cell systems although they had no effect on the subunit assembly. We found that mutated receptors accumulated in the ER where they were shown to associate with chaperones calnexin, BiP and Grp94. However, their surface expression was increased when ER-associated degradation or proteosome function was inhibited, while modulation of ER calcium stores had little effect. When compared to the wild-type, mutated receptors showed decreased interaction with calnexin, similar binding to BiP and increased association with Grp94. Structural modelling of calnexin interaction with the wt or mutated GABAAR revealed that disruption in structure caused by mutations in the conserved region adjoining the TM1 may impair calnexin binding. Thus, this previously uncharacterised region plays an important role in intracellular processing of GABAARs at least in part by stabilizing their interaction with calnexin.

Type: Article
Title: Control of cell surface expression of GABAA receptors by a conserved region at the end of the N-terminal extracellular domain of receptor subunits
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jbc.2022.102590
Publisher version: https://doi.org/10.1016/j.jbc.2022.102590
Language: English
Additional information: This is an Open Access article published under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: GABA receptor, N‐linked glycosylation, calnexin, endoplasmic reticulum (ER), homology modelling, intracellular trafficking, molecular chaperone, mutagenesis, protein‐protein interaction
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10158051
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