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A Coupled Array of Noncovalent Interactions Impacts the Function of the 5‑HT_3A Serotonin Receptor in an Agonist-Specific Way

Miles, Timothy F. and Bower, Kiowa S. and Lester, Henry A. and Dougherty, Dennis A. (2012) A Coupled Array of Noncovalent Interactions Impacts the Function of the 5‑HT_3A Serotonin Receptor in an Agonist-Specific Way. ACS Chemical Neuroscience, 3 (10). pp. 753-760. ISSN 1948-7193. PMCID PMC3474281. doi:10.1021/cn3000586. https://resolver.caltech.edu/CaltechAUTHORS:20121127-103848210

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Abstract

The serotonin type 3A (5-HT_3A) receptor is a Cys-loop (pentameric) neurotransmitter-gated ion channel found in the central and peripheral nervous systems and implicated in numerous diseases. In previous studies with the endogenous agonist serotonin, we identified two interactions critical for receptor function: a cation−π interaction with W183 in loop B (TrpB) and a hydrogen bond to E129 in loop A. Here we employ mutant cycle analyses utilizing conventional and unnatural amino acid mutagenesis to demonstrate that a third residue, D124 of loop A, forms two functionally important hydrogen bonds to the backbone of loop B. We also show that these three interactions, the cation−π interaction, the backbone hydrogen bonds, and the E129 hydrogen bond, are tightly coupled to each other, suggesting they function as a single unit. We also identify key functional differences between serotonin and the competitive partial agonist m-chlorophenyl biguanide (mCPBG) at these residues. mCPBG displays no cation−π at TrpB and extreme sensitivity to the positioning of E129, on which it is reliant for initiation of channel gating.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/cn3000586DOIArticle
http://pubs.acs.org/doi/abs/10.1021/cn3000586PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474281PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2012 American Chemical Society. Received: May 30, 2012. Accepted: July 20, 2012. Publication Date (Web): July 20, 2012. Author Contributions: T.F.M., K.S.B., H.A.L., and D.A.D. contributed to research design. T.F.M. and K.S.B. conducted experiments. T.F.M., K.S.B., H.A.L., and D.A.D. performed data analysis. T.F.M., K.S.B., H.A.L., and D.A.D. wrote the manuscript. The authors declare no competing financial interest. We thank Dr. Sarah Lummis (Cambridge) for helpful discussions and Noah Duffy for the preparation of 4,7-F2-Trp. This work was supported by the NIH (NS 34407 to D.A.D.).
Funders:
Funding AgencyGrant Number
NIHNS 34407
Subject Keywords:Serotonin, mCPBG, Cys-loop, binding site, gating, unnatural amino acid mutagenesis
Issue or Number:10
PubMed Central ID:PMC3474281
DOI:10.1021/cn3000586
Record Number:CaltechAUTHORS:20121127-103848210
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20121127-103848210
Official Citation: A Coupled Array of Noncovalent Interactions Impacts the Function of the 5-HT3A Serotonin Receptor in an Agonist-Specific Way Timothy F. Miles, Kiowa S. Bower, Henry A. Lester, and Dennis A. Dougherty ACS Chemical Neuroscience 2012 3 (10), 753-760
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35670
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:27 Nov 2012 18:55
Last Modified:09 Nov 2021 23:16

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