Journal Article


The fifth subunit of the (α4β2)2β2 nicotinic acetylcholine receptor modulates maximal ACh responses

Abstract

BACKGROUND AND PURPOSE: The fifth subunit in the (α4β2)2α4 nicotinic acetylcholine receptor (nAChR) plays a determining role in the pharmacology of this nAChR type. Here, we have examined the role of the fifth subunit in the ACh responses of the (α4β2)2β2 nAChR type. EXPERIMENTAL APPROACH: The role of the fifth subunit in receptor function was explored using two-electrode voltage-clamp electrophysiology, along with subunit-targeted mutagenesis and the substituted cysteine scanning method applied to fully linked (α4β2)2β2 receptors. KEY RESULTS: Covalent modification of cysteine substituted fifth subunit with a thiol-reactive agent (MTS) caused irreversible inhibition of receptor function. ACh reduced the rate of MTS reaction but the competitive inhibitor dihydro-β-erythroidine had no effect. Alanine substitution of conserved residues that line the core of agonist sites on α4(+)/β2(-) interfaces did not impair receptor function. However, impairment of agonist binding to α4(+)/β2(-) agonist sites by mutagenesis modified the effect of ACh on the rate of MTS reaction. The extent of this effect was dependent on the position of the agonist site relative to the fifth subunit. CONCLUSIONS AND IMPLICATIONS: We conclude that the fifth subunit in (α4β2)2β2 receptor isoform modulates maximal ACh responses. This effect appears to be driven by a modulatory, and asymmetric, association with the α4(+)/β2(-) agonist sites.

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Authors

New, Karina
Garcia del Villar, Silvia
Fazzaferro, Simone
Alcaino, Constanza
Bermudez, Isabel

Oxford Brookes departments

Faculty of Health and Life Sciences\Department of Biological and Medical Sciences

Dates

Year of publication: 2017
Date of RADAR deposit: 2017-06-07


Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License


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