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Selective Ligand Behaviors Provide New Insights into Agonist Activation of Nicotinic Acetylcholine Receptors

Marotta, Christopher B. and Rreza, Iva and Lester, Henry A. and Dougherty, Dennis A. (2014) Selective Ligand Behaviors Provide New Insights into Agonist Activation of Nicotinic Acetylcholine Receptors. ACS Chemical Biology, 9 (5). pp. 1153-1159. ISSN 1554-8929. PMCID PMC4033646. doi:10.1021/cb400937d.

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Nicotinic acetylcholine receptors are a diverse set of ion channels that are essential to everyday brain function. Contemporary research studies selective activation of individual subtypes of receptors, with the hope of increasing our understanding of behavioral responses and neurodegenerative diseases. Here, we aim to expand current binding models to help explain the specificity seen among three activators of α4β2 receptors: sazetidine-A, cytisine, and NS9283. Through mutational analysis, we can interchange the activation profiles of the stoichiometry-selective compounds sazetidine-A and cytisine. In addition, mutations render NS9283—currently identified as a positive allosteric modulator—into an agonist. These results lead to two conclusions: (1) occupation at each primary face of an α subunit is needed to activate the channel and (2) the complementary face of the adjacent subunit dictates the binding ability of the agonist.

Item Type:Article
Related URLs:
URLURL TypeDescription Information CentralArticle
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2014 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: December 20, 2013; Accepted: February 24, 2014; Published: February 24, 2014. We thank the National Institutes of Health (NIH) (NS034407, DA017279, DA280382), NIH/NRSA (GM07616), and the California Tobacco-Related Disease Research Program from the University of California (19XT-0102) for support of this work. The authors declare no competing financial interest.
Funding AgencyGrant Number
NIH Predoctoral FellowshipGM07616
California Tobacco-Related Disease Research Program19XT-0102
Issue or Number:5
PubMed Central ID:PMC4033646
Record Number:CaltechAUTHORS:20170302-160217090
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Official Citation:Selective Ligand Behaviors Provide New Insights into Agonist Activation of Nicotinic Acetylcholine Receptors Christopher B. Marotta, Iva Rreza, Henry A. Lester, and Dennis A. Dougherty ACS Chemical Biology 2014 9 (5), 1153-1159 DOI: 10.1021/cb400937d
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74673
Deposited By: Tony Diaz
Deposited On:03 Mar 2017 03:14
Last Modified:11 Nov 2021 05:29

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