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Binding Interactions with the Complementary Subunit of Nicotinic Receptors

Blum, Angela P. and Van Arnam, Ethan B. and German, Laurel A. and Lester, Henry A. and Dougherty, Dennis A. (2013) Binding Interactions with the Complementary Subunit of Nicotinic Receptors. Journal of Biological Chemistry, 288 (10). pp. 6991-6997. ISSN 0021-9258. PMCID PMC3591609. doi:10.1074/jbc.M112.439968. https://resolver.caltech.edu/CaltechAUTHORS:20130411-103637479

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Abstract

The agonist-binding site of nicotinic acetylcholine receptors (nAChRs) spans an interface between two subunits of the pentameric receptor. The principal component of this binding site is contributed by an α subunit, and it binds the cationic moiety of the nicotinic pharmacophore. The other part of the pharmacophore, a hydrogen bond acceptor, has recently been shown to bind to the complementary non-α subunit via the backbone NH of a conserved Leu. This interaction was predicted by studies of ACh-binding proteins and confirmed by functional studies of the neuronal (CNS) nAChR, α4β2. The ACh-binding protein structures further suggested that the hydrogen bond to the backbone NH is mediated by a water molecule and that a second hydrogen bonding interaction occurs between the water molecule and the backbone CO of a conserved Asn, also on the non-α subunit. Here, we provide new insights into the nature of the interactions between the hydrogen bond acceptor of nicotinic agonists and the complementary subunit backbone. We studied both the nAChR of the neuromuscular junction (muscle-type) and a neuronal subtype, (α4)2(β4)3. In the muscle-type receptor, both ACh and nicotine showed a strong interaction with the Leu NH, but the potent nicotine analog epibatidine did not. This interaction was much attenuated in the α4β4 receptor. Surprisingly, we found no evidence for a functionally significant interaction with the backbone carbonyl of the relevant Asn in either receptor with an array of agonists.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1074/jbc.M112.439968DOIArticle
http://www.jbc.org/content/288/10/6991PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591609/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2013 American Society for Biochemistry and Molecular Biology, Inc. Received for publication, November 26, 2012, and in revised form, January 23, 2013. Published, JBC Papers in Press, January 24, 2013. This work was supported, in whole or in part, by National Institutes of Health Grants NS34407 and NS11756. This work was also supported by Tobacco-Related Disease Research Program Award 19XT-0102 from the University of California. Acknowledgment—We thank Pfizer for the generous gift of varenicline.
Funders:
Funding AgencyGrant Number
NIHNS34407
NIHNS11756
California Tobacco-Related Disease Research Program19XT-0102
Issue or Number:10
PubMed Central ID:PMC3591609
DOI:10.1074/jbc.M112.439968
Record Number:CaltechAUTHORS:20130411-103637479
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130411-103637479
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37887
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:11 Apr 2013 20:09
Last Modified:09 Nov 2021 23:32

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