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A conserved arginine with non-conserved function is a key determinant of agonist selectivity in αβββ7 nicotinic acetylcholine receptors
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  • Teresa Minguez,
  • Beatriz Neilsen,
  • Deborah Shoemark,
  • Cecilia Gotti,
  • Richard Sessions,
  • Adrian Mulholland,
  • Cecilia Bouzat,
  • Susan Wonnacott,
  • Tim Gallagher,
  • Isabel Bermudez,
  • Ana Oliveira
Teresa Minguez
Oxford Brookes University

Corresponding Author:[email protected]

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Beatriz Neilsen
Universidad Nacional del Sur Departamento de Biología Bioquímica y Farmacia
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Deborah Shoemark
University of Bristol
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Cecilia Gotti
Consiglio Nazionale delle Ricerche
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Richard Sessions
University of Bristol
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Adrian Mulholland
University of Bristol
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Cecilia Bouzat
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Susan Wonnacott
University of Bath
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Tim Gallagher
University of Bristol
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Isabel Bermudez
Oxford Brookes University
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Ana Oliveira
University of Bristol
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BACKGROUND AND PURPOSE: The α7 and α4β2* (* denotes possibly assembly with another subunit) nicotinic acetylcholine receptors (nAChR) are the most abundant nAChR in the mammalian brain. These subtypes are also the most commonly targeted nAChR in drug discovery programs for brain disorders. However, the development of subtype-specific agonists remains challenging, mainly due to the high degree of sequence homology coupled to the conservation of function in the nAChR family. Here, we determined the structural underpinning of the selectivity of 10-methylcytisine, a compound with high-affinity for α4β2* nAChR but negligible selectivity for the α7 subtype. EXPERIMENTAL APPROACH: The structural underpinning of the receptor selectivity of 10-methylcytisine was investigated using molecular dynamics simulations combined with mutagenesis and whole-cell and single-channel current recordings. KEY RESULTS: We identify a conserved arginine residue in the β3-strand that exhibits a non-conserved salt-bridge in the nAChR family. In α4β2 nAChR, the arginine forms an inter-subunit salt-bridge with an aspartate residue in loop B that is necessary for functional expression, whereas in the α7 subtype, this residue is not stabilised by electrostatic interactions, making its side chain highly mobile. This produces steric clashes with agonists and affects the dynamics of residues involved in agonist binding or the coupling network. CONCLUSIONS AND IMPLICATIONS: We conclude that the high mobility of the arginine residue in the α7 nAChR subtype affects agonist function by influencing agonist binding and the pathway communicating agonist binding to the ion channel. The findings have implications for the rational design of subtype-selective cholinergic agents.
03 Sep 2020Submitted to British Journal of Pharmacology
04 Sep 2020Submission Checks Completed
04 Sep 2020Assigned to Editor
08 Sep 2020Reviewer(s) Assigned
27 Sep 2020Review(s) Completed, Editorial Evaluation Pending
20 Oct 2020Editorial Decision: Revise Minor
13 Dec 20201st Revision Received
15 Dec 2020Submission Checks Completed
15 Dec 2020Assigned to Editor
15 Dec 2020Reviewer(s) Assigned
29 Dec 2020Review(s) Completed, Editorial Evaluation Pending
12 Jan 2021Editorial Decision: Accept