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Annual Review of Biochemistry

Volume 93, 2024

The Nicotinic Acetylcholine Receptor and Its Pentameric Homologs: Toward an Allosteric Mechanism of Signal Transduction at the Atomic Level

  • Marco Cecchini1, Pierre-Jean Corringer2 and Jean-Pierre Changeux3
  • 1Institut de Chimie de Strasbourg, CNRS UMR 7177, Université de Strasbourg, Strasbourg, France 2Channel Receptors Unit, Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Paris, France 3Department of Neuroscience, Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Paris, France; email: [email protected]
  • Vol. 93:339-366 (Volume publication date August 2024)
  • First published as a Review in Advance on February 12, 2024
  • Copyright © 2024 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography and high-resolution cryo–electron microscopy, together with molecular dynamic simulations of nicotinic receptors and homologs, have opened a new era in the understanding of channel gating by the neurotransmitter. They reveal, at atomic resolution, the diversity and flexibility of the multiple ligand-binding sites, including recently discovered allosteric modulatory sites distinct from the neurotransmitter orthosteric site, and the conformational dynamics of the activation process as a molecular switch linking these multiple sites. The model emerging from these studies paves the way for a new pharmacology based, first, upon the occurrence of an original mode of indirect allosteric modulation, distinct from a steric competition for a single and rigid binding site, and second, the design of drugs that specifically interact with privileged conformations of the receptor such as agonists, antagonists, and desensitizers. Research on nicotinic receptors is still at the forefront of understanding the mode of action of drugs on the nervous system.

Keyword(s): allosteric regulation, brain disorders, neuropharmacology, nicotinic acetylcholine receptor, signal transduction mechanism, synaptic receptors
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/content/journals/10.1146/annurev-biochem-030122-033116
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The Nicotinic Acetylcholine Receptor and Its Pentameric Homologs: Toward an Allosteric Mechanism of Signal Transduction at the Atomic Level
Annual Review of Biochemistry 93, 339 (2024); https://doi.org/10.1146/annurev-biochem-030122-033116
/content/journals/10.1146/annurev-biochem-030122-033116
/content/journals/10.1146/annurev-biochem-030122-033116
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