Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan
Version of Record online: 31 JAN 2013
© 2013 The Authors Journal of Neurochemistry © 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 125, Issue 1, pages 7–15, April 2013
How to Cite
J. Neurochem. (2013) 125, 7–15.
- Issue online: 21 MAR 2013
- Version of Record online: 31 JAN 2013
- Accepted manuscript online: 10 JAN 2013 08:48AM EST
- Manuscript Accepted: 7 JAN 2013
- Manuscript Revised: 10 DEC 2012
- Manuscript Received: 13 SEP 2012
- Ministry of Education, Culture, Sports, Science and Technology of Japan
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.