Journal Article


alpha 4 beta 2 Nicotinic Acetylcholine Receptors: Relationships Between Subunit Stoichiometry and Function at the Single Channel Level

Abstract

Acetylcholine receptors comprising alpha 4 and beta 2 subunits are the most abundant class of nicotinic acetylcholine receptor in the brain. They contribute to cognition, reward, mood, and nociception and are implicated in a range of neurological disorders. Previous measurements of whole-cell macroscopic currents showed that alpha 4 and beta 2 subunits assemble in two predominant pentameric stoichiometries, which differ in their sensitivity to agonists, antagonists, and allosteric modulators. Here we compare agonist-elicited single channel currents from receptors assembled with an excess of either the alpha 4 or beta 2 subunit, forming receptor populations biased toward one or the other stoichiometry, with currents from receptors composed of five concatemeric subunits in which the subunit stoichiometry is predetermined. Our results associate each subunit stoichiometry with a unique single channel conductance, mean open channel lifetime, and sensitivity to the allosteric potentiator 3-[3-(3-pyridinyl)-1,2,4-oxadiazol-5-yl] benzonitrile (NS-9283). Receptors with the composition (alpha 4 beta 2)(2)alpha 4 exhibit high single channel conductance, brief mean open lifetime, and strong potentiation by NS-9283, whereas receptors with the composition (alpha 4 beta 2)(2)beta 2 exhibit low single channel conductance and long mean open lifetime and are not potentiated by NS-9283. Thus single channel current measurements reveal bases for the distinct functional and pharmacological properties endowed by different stoichiometries of alpha 4 and beta 2 subunits and establish pentameric concatemers as a means to delineate interactions between subunits that confer these properties.

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Authors

Mazzaferro, Simone
Bermudez, Isabel
Sine, Steven M.

Oxford Brookes departments

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

Dates

Year of publication: 2016
Date of RADAR deposit: 2017-04-11


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


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