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Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan.
- Source :
-
Journal of neurochemistry [J Neurochem] 2013 Apr; Vol. 125 (1), pp. 7-15. Date of Electronic Publication: 2013 Jan 31. - Publication Year :
- 2013
-
Abstract
- The 5-hydroxytryptamine (serotonin, 5-HT) type 3 (5-HT3) receptor belongs to the superfamily of Cys-loop ligand-gated ion channels, and can be either homopentameric (5-HT3A) or heteropentameric (5-HT3AB) receptor. Several modulators are known, which either inhibit or potentiate this channel, but few have any appreciable selectivity between the two subtypes or can modulate one receptor differently to the other. In this study, we show that the anticancer drug, topotecan, bidirectionally modulates the 5-HT3 receptor using a two-electrode voltage clamp technique. Topotecan inhibited 5-HT-gated current through homomeric 5-HT3A receptors. Interestingly, however, additional expression of the 5-HT3B subunit changed the response to topotecan dramatically from an inhibitory to a potentiatory one. This effect was dependent on the level of 5-HT3B subunit expression. Moreover, the effect was reduced in the receptors containing the 5-HT3B(Y129S) polymorphic variant. These finding could explain individual differences in the sensitivity to topotecan-induced nausea and vomiting.<br /> (© 2013 The Authors Journal of Neurochemistry © 2013 International Society for Neurochemistry.)
- Subjects :
- Animals
Female
Humans
In Vitro Techniques
Mutation
Oocytes drug effects
Oocytes physiology
Patch-Clamp Techniques
Polymorphism, Genetic
Protein Subunits genetics
Receptors, Serotonin, 5-HT3 genetics
Xenopus laevis
Antineoplastic Agents pharmacology
Protein Subunits physiology
Receptors, Serotonin, 5-HT3 physiology
Serotonin 5-HT3 Receptor Agonists pharmacology
Serotonin 5-HT3 Receptor Antagonists pharmacology
Topotecan pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1471-4159
- Volume :
- 125
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23305320
- Full Text :
- https://doi.org/10.1111/jnc.12146