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Activation of human 5-hydroxytryptamine type 3 receptors via an allosteric transmembrane site.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2015 Jan; Vol. 87 (1), pp. 87-95. Date of Electronic Publication: 2014 Oct 22. - Publication Year :
- 2015
-
Abstract
- In common with other members of the Cys-loop family of pentameric ligand-gated ion channels, 5-hydroxytryptamine type 3 receptors (5-HT3Rs) are activated by the binding of a neurotransmitter to an extracellular orthosteric site, located at the interface of two adjacent receptor subunits. In addition, a variety of compounds have been identified that modulate agonist-evoked responses of 5-HT3Rs, and other Cys-loop receptors, by binding to distinct allosteric sites. In this study, we examined the pharmacological effects of a group of monoterpene compounds on recombinant 5-HT3Rs expressed in Xenopus oocytes. Two phenolic monoterpenes (carvacrol and thymol) display allosteric agonist activity on human homomeric 5-HT3ARs (64 ± 7% and 80 ± 4% of the maximum response evoked by the endogenous orthosteric agonist 5-HT, respectively). In addition, at lower concentrations, where agonist effects are less apparent, carvacrol and thymol act as potentiators of responses evoked by submaximal concentrations of 5-HT. By contrast, carvacrol and thymol have no agonist or potentiating activity on the closely related mouse 5-HT3ARs. Using subunit chimeras containing regions of the human and mouse 5-HT3A subunits, and by use of site-directed mutagenesis, we have identified transmembrane amino acids that either abolish the agonist activity of carvacrol and thymol on human 5-HT3ARs or are able to confer this property on mouse 5-HT3ARs. By contrast, these mutations have no significant effect on orthosteric activation of 5-HT3ARs by 5-HT. We conclude that 5-HT3ARs can be activated by the binding of ligands to an allosteric transmembrane site, a conclusion that is supported by computer docking studies.<br /> (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)
- Subjects :
- Amino Acids
Animals
Binding Sites
Cymenes
Drug Synergism
HEK293 Cells
Humans
Mice
Molecular Docking Simulation
Mutagenesis, Site-Directed
Receptors, Serotonin, 5-HT3 genetics
Species Specificity
Thymol pharmacology
Xenopus laevis genetics
Monoterpenes pharmacology
Receptors, Serotonin, 5-HT3 metabolism
Serotonin 5-HT3 Receptor Agonists pharmacology
Xenopus laevis embryology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0111
- Volume :
- 87
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25338672
- Full Text :
- https://doi.org/10.1124/mol.114.094540