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Two Neuronal Nicotinic Acetylcholine Receptors, α4β4 and α7, Show Differential Agonist Binding Modes

Puskar, Nyssa L. and Xiu, Xinan and Lester, Henry A. and Dougherty, Dennis A. (2011) Two Neuronal Nicotinic Acetylcholine Receptors, α4β4 and α7, Show Differential Agonist Binding Modes. Journal of Biological Chemistry, 286 (16). pp. 14618-14627. ISSN 0021-9258. PMCID PMC3077659. doi:10.1074/jbc.M110.206565. https://resolver.caltech.edu/CaltechAUTHORS:20110502-112328466

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Abstract

Nicotinic acetylcholine receptors (nAChRs) are pentameric, neurotransmitter-gated ion channels responsible for rapid excitatory neurotransmission in the central and peripheral nervous systems, resulting in skeletal muscle tone and various cognitive effects in the brain. These complex proteins are activated by the endogenous neurotransmitter ACh as well as by nicotine and structurally related agonists. Activation and modulation of nAChRs has been implicated in the pathology of multiple neurological disorders, and as such, these proteins are established therapeutic targets. Here we use unnatural amino acid mutagenesis to examine the ligand binding mechanisms of two homologous neuronal nAChRs: the α4β4 and α7 receptors. Despite sequence identity among the residues that form the core of the agonist-binding site, we find that the α4β4 and α7 nAChRs employ different agonist-receptor binding interactions in this region. The α4β4 receptor utilizes a strong cation-π interaction to a conserved tryptophan (TrpB) of the receptor for both ACh and nicotine, and nicotine participates in a strong hydrogen bond with a backbone carbonyl contributed by TrpB. Interestingly, we find that the α7 receptor also employs a cation-π interaction for ligand recognition, but the site has moved to a different aromatic amino acid of the agonist-binding site depending on the agonist. ACh participates in a cation-π interaction with TyrA, whereas epibatidine participates in a cation-π interaction with TyrC2.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1074/jbc.M110.206565DOIArticle
http://www.jbc.org/content/286/16/14618PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077659/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2011 American Society for Biochemistry and Molecular Biology. Received for publication, November 24, 2010, and in revised form, January 25, 2011. Published, JBC Papers in Press, February 22, 2011. This work was supported, in whole or in part, by National Institutes of Health Grants NS 34407 and NS 11756.
Funders:
Funding AgencyGrant Number
NIHNS 34407
NIHNS 11756
Subject Keywords:Drug Design; Nicotinic Acetylcholine Receptors; Protein Chemical Modification; Protein Drug Interactions; Protein Structure; Cation-π; Interaction; Unnatural Amino Acid Mutagenesis
Issue or Number:16
PubMed Central ID:PMC3077659
DOI:10.1074/jbc.M110.206565
Record Number:CaltechAUTHORS:20110502-112328466
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20110502-112328466
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:23522
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:03 May 2011 17:07
Last Modified:09 Nov 2021 16:15

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