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Probing the non-canonical interface for agonist interaction with an α5 containing nicotinic acetylcholine receptor

Marotta, Christopher B. and Dilworth, Crystal N. and Lester, Henry A. and Dougherty, Dennis A. (2014) Probing the non-canonical interface for agonist interaction with an α5 containing nicotinic acetylcholine receptor. Neuropharmacology, 77 . pp. 342-349. ISSN 0028-3908. PMCID PMC3934363. http://resolver.caltech.edu/CaltechAUTHORS:20140227-142503676

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Abstract

Nicotinic acetylcholine receptors (nAChRs) containing the α5 subunit are of interest because genomewide association studies and candidate gene studies have identified polymorphisms in the α5 gene that are linked to an increased risk for nicotine dependence, lung cancer, and/or alcohol addiction. To probe the functional impact of an α5 subunit on nAChRs, a method to prepare a homogeneous population of α5-containing receptors must be developed. Here we use a gain of function (9') mutation to isolate populations of α5-containing nAChRs for characterization by electrophysiology. We find that the α5 subunit modulates nAChR rectification when co-assembled with α4 and β2 subunits. We also probe the α5-α4 interface for possible ligand-binding interactions. We find that mutations expected to ablate an agonist-binding site involving the α5 subunit have no impact on receptor function. The most straightforward interpretation of this observation is that agonists do not bind at the α5-α4 interface, in contrast to what has recently been demonstrated for the α4-α4 interface in related receptors. In addition, our mutational results suggest that the α5 subunit does not replace the α4 or β2 subunits and is relegated to occupying only the auxiliary position of the pentameric receptor.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.neuropharm.2013.09.028DOIArticle
http://www.sciencedirect.com/science/article/pii/S0028390813004747PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934363PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2013 Elsevier Ltd. Received 19 July 2013; Received in revised form 25 September 2013; Accepted 30 September 2013. We thank Bruce N. Cohen for help with data interpretation. This work was supported by grants from the NIH (NS034407, DA017279, DA280382), NIH/NRSA (GM07616) and the California Tobacco-Related Disease Research Program from the University of California (19XT-0102).
Funders:
Funding AgencyGrant Number
NIHNS034407
NIHDA017279
NIHDA280382
NIH Predoctoral FellowshipGM07616
University of California California Tobacco-Related Disease Research Program19XT-0102
Subject Keywords:Addiction; Biophysics; Cholinergic receptor; Electrophysiology; Ion channels; Nicotinic acetylcholine receptors
PubMed Central ID:PMC3934363
Record Number:CaltechAUTHORS:20140227-142503676
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20140227-142503676
Official Citation:Marotta, C. B., Dilworth, C. N., Lester, H. A., & Dougherty, D. A. (2014). Probing the non-canonical interface for agonist interaction with an α5 containing nicotinic acetylcholine receptor. Neuropharmacology, 77(0), 342-349. doi: http://dx.doi.org/10.1016/j.neuropharm.2013.09.028
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44042
Collection:CaltechAUTHORS
Deposited By: Aucoeur Ngo
Deposited On:28 Feb 2014 15:40
Last Modified:03 Nov 2017 21:54

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