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Allosteric activation of the 5-HT_3AB receptor by mCPBG

Miles, Timothy F. and Lester, Henry A. and Dougherty, Dennis A. (2015) Allosteric activation of the 5-HT_3AB receptor by mCPBG. Neuropharmacology, 91 . pp. 103-108. ISSN 0028-3908. PMCID PMC4312754. doi:10.1016/j.neuropharm.2014.12.018.

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The 5-HT_3AB receptor contains three A and two B subunits in an A-A-B-A-B order. However, serotonin function at the 5-HT_3AB receptor has been shown to depend solely on the A-A interface present in the homomeric receptor. Using mutations at sites on both the primary (E122) and complementary (Y146) faces of the B subunit, we demonstrate that meta-chlorophenyl biguanide (mCPBG), a 5-HT_3 selective agonist, is capable of binding to and activating the 5-HT_3AB receptor at all five subunit interfaces of the heteromer. Further, mCPBG is capable of allosterically modulating the activity of serotonin from these sites. While these five binding sites are similar enough that they form to a monophasic dose – response relationship, we uncover subtle differences in the heteromeric binding sites. We also find that the A-A interface appears to contribute disproportionately to the efficacy of 5-HT_3AB receptor activation.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2014 Published by Elsevier Ltd. Received 8 July 2014. Received in revised form 16 October 2014. Accepted 10 December 2014. Available online 23 December 2014. We would like to thank Dr. Sarah Lummis (Cambridge) and Dr. Noah Duffy for helpful discussion. This work was supported by the NIH (NS 34407).
Funding AgencyGrant Number
NIHNS 34407
Subject Keywords: mCPBG; Serotonin; 5-HT3; Allosteric modulation; Cys-loop receptor
PubMed Central ID:PMC4312754
Record Number:CaltechAUTHORS:20150106-073218861
Persistent URL:
Official Citation:Timothy F. Miles, Henry A. Lester, Dennis A. Dougherty, Allosteric activation of the 5-HT3AB receptor by mCPBG, Neuropharmacology, Volume 91, April 2015, Pages 103-108, ISSN 0028-3908, ( (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:53197
Deposited By: Ruth Sustaita
Deposited On:06 Jan 2015 18:25
Last Modified:10 Nov 2021 19:49

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