title: Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan.
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.
authors.affiliation: Department of Neuroscience and Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. ynakamura@anat1.med.osaka-u.ac.jp
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ishida
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamada
authors.forename: Makoto
authors.initials: M
authors.lastname: Kondo
authors.forename: Shoichi
authors.initials: S
authors.lastname: Shimada
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011110:Polymorphism, Genetic; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology*; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000502:physiology*; D058827:Serotonin 5-HT3 Receptor Agonists / Q000494:pharmacology*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology*; D019772:Topotecan / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D000970:Antineoplastic Agents; D021122:Protein Subunits; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D019772:Topotecan