UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Benzodiazepines Modulate GABAA Receptors by Regulating the Preactivation Step after GABA Binding

Gielen, MC; Lumb, MJ; Smart, TG; (2012) Benzodiazepines Modulate GABAA Receptors by Regulating the Preactivation Step after GABA Binding. Journal of Neuroscience , 32 (17) 5707 - 5715. 10.1523/JNEUROSCI.5663-11.2012. Green open access

[img]
Preview
PDF
Gielen, J Neurosci, 2012.pdf
Available under License : See the attached licence file.

Download (434kB)

Abstract

GABAA receptors (GABAARs) composed of αβγ subunits are allosterically modulated by the benzodiazepines (BDZs). Agonists at the BDZ binding site potentiate submaximal GABA responses by increasing the apparent affinity of GABAARs for GABA. Although BDZs were initially thought to affect the binding of GABA agonists, recent studies suggest an effect on receptor gating; however, the involvement of preactivation steps in the modulation by BDZs has not been considered. Consequently, we examined whether BDZ agonists could exert their modulatory effect by displacing the equilibrium between resting and preactivated states of recombinant α1β2γ2 GABAARs expressed in Xenopus oocytes. For GABA and the partial agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol and piperidine-4-sulfonic acid, we examined BDZ modulation using a simple three-step model incorporating agonist binding, receptor preactivation, and channel opening. The model accounted for diazepam modulation simply by increasing the preactivation constant by approximately fourfold. To assess whether BDZs preferentially affected a specific GABA binding site, pentameric concatamers were used. This demonstrated that single GABA-binding site mutant receptors were equally sensitive to modulation by BDZs compared with wild-type counterparts. Overall, our results suggest that BDZs affect the preactivation step to cause a global conformational rearrangement of GABAARs, thereby modulating receptor function.

Type: Article
Title: Benzodiazepines Modulate GABAA Receptors by Regulating the Preactivation Step after GABA Binding
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.5663-11.2012
Publisher version: http://dx.doi.org/10.1523/JNEUROSCI.5663-11.2012
Language: English
Additional information: Copyright © 2012 the authors. After 6 months from the date of publication this work becomes available to the public to copy, distribute, or display under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license. For more information please see http://creativecommons.org/licenses/by-nc-sa/3.0/
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/1344170
Downloads since deposit
153Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item