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Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function

Boffi, JC; Marcovich, I; Gill-Thind, JK; Corradi, J; Collins, T; Lipovsek, MM; Moglie, M; ... Elgoyhen, AB; + view all (2017) Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function. Molecular Pharmacology , 91 (3) pp. 250-262. 10.1124/mol.116.107482. Green open access

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Abstract

Nicotinic acetylcholine receptors can be assembled from either homomeric or heteromeric pentameric subunit combinations. At the interface of the extracellular domains of adjacent subunits lies the acetylcholine binding site, composed of a principal component provided by one subunit and a complementary component of the adjacent subunit. Compared to neuronal nAChRs assembled from α and β subunits, the α9α10 receptor is an atypical member of the family. It is a heteromeric receptor composed only of α subunits. Whereas mammalian α9 subunits can form functional homomeric α9 receptors, α10 subunits do not generate functional channels when expressed heterologously. Hence, it has been proposed that α10 might serve as a "structural" subunit, much like a β subunit of heteromeric nAChRs, providing only complementary components to the agonist binding site. Here we have made use of site-directed mutagenesis to examine the contribution of subunit interface domains to α9α10 receptors by a combination of electrophysiological and radioligand binding studies. Characterization of receptors containing Y190T mutations revealed unexpectedly that both α9 and α10 subunits equally contribute to principal components of the α9α10 nAChR. In addition we have shown that the introduction of a W55T mutation impairs receptor binding and function in the rat α9 subunit but not in the α10 subunit, indicating that the contribution of α9 and α10 subunits to complementary components of the ligand-binding site is non-equivalent. We conclude that this asymmetry, which is supported by molecular docking studies, results from adaptive amino acid changes acquired only during the evolution of mammalian α10 subunits.

Type: Article
Title: Differential contribution of subunit interfaces to α9α10 nicotinic acetylcholine receptor function
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1124/mol.116.107482
Publisher version: http://dx.doi.org/10.1124/mol.116.107482
Language: English
Additional information: Copyright © 2017 by The Author(s) This is an open access article distributed under the CC-BY Attribution 4.0 International license.
Keywords: Nicotinic cholinergic, Structure determinations
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
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 > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1535944
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