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Ligand Binding at the α4-α4 Agonist-Binding Site of the α4β2 nAChR Triggers Receptor Activation through a Pre-Activated Conformational State

Author

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  • Dinesh C Indurthi
  • Trevor M Lewis
  • Philip K Ahring
  • Thomas Balle
  • Mary Chebib
  • Nathan L Absalom

Abstract

The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant subtype in the brain and exists in two functional stoichiometries: (α4)3(β2)2 and (α4)2(β2)3. A distinct feature of the (α4)3(β2)2 receptor is the biphasic activation response to the endogenous agonist acetylcholine, where it is activated with high potency and low efficacy when two α4-β2 binding sites are occupied and with low potency/high efficacy when a third α4-α4 binding site is occupied. Further, exogenous ligands can bind to the third α4-α4 binding site and potentiate the activation of the receptor by ACh that is bound at the two α4-β2 sites. We propose that perturbations of the recently described pre-activation step when a third binding site is occupied are a key driver of these distinct activation properties. To investigate this, we used a combination of simple linear kinetic models and voltage clamp electrophysiology to determine whether transitions into the pre-activated state were increased when three binding sites were occupied. We separated the binding at the two different sites with ligands selective for the α4-β2 site (Sazetidine-A and TC-2559) and the α4-α4 site (NS9283) and identified that when a third binding site was occupied, changes in the concentration-response curves were best explained by an increase in transitions into a pre-activated state. We propose that perturbations of transitions into a pre-activated state are essential to explain the activation properties of the (α4)3(β2)2 receptor by acetylcholine and other ligands. Considering the widespread clinical use of benzodiazepines, this discovery of a conserved mechanism that benzodiazepines and ACh potentiate receptor activation via a third binding site can be exploited to develop therapeutics with similar properties at other cys-loop receptors.

Suggested Citation

  • Dinesh C Indurthi & Trevor M Lewis & Philip K Ahring & Thomas Balle & Mary Chebib & Nathan L Absalom, 2016. "Ligand Binding at the α4-α4 Agonist-Binding Site of the α4β2 nAChR Triggers Receptor Activation through a Pre-Activated Conformational State," PLOS ONE, Public Library of Science, vol. 11(8), pages 1-20, August.
  • Handle: RePEc:plo:pone00:0161154
    DOI: 10.1371/journal.pone.0161154
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    References listed on IDEAS

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    1. Remigijus Lape & David Colquhoun & Lucia G. Sivilotti, 2008. "On the nature of partial agonism in the nicotinic receptor superfamily," Nature, Nature, vol. 454(7205), pages 722-727, August.
    2. Claudio Grosman & Ming Zhou & Anthony Auerbach, 2000. "Mapping the conformational wave of acetylcholine receptor channel gating," Nature, Nature, vol. 403(6771), pages 773-776, February.
    3. Nuriya Mukhtasimova & Won Yong Lee & Hai-Long Wang & Steven M. Sine, 2009. "Detection and trapping of intermediate states priming nicotinic receptor channel opening," Nature, Nature, vol. 459(7245), pages 451-454, May.
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