Premium
Subunit‐dependent inhibition and potentiation of 5‐ HT 3 receptor by the anticancer drug, topotecan
Author(s) -
Nakamura Yukiko,
Ishida Yusuke,
Yamada Takahiro,
Kondo Makoto,
Shimada Shoichi
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12146
Subject(s) - topotecan , homomeric , receptor , pharmacology , chemistry , 5 ht3 receptor , 5 ht receptor , long term potentiation , agonist , protein subunit , serotonin , biology , biochemistry , medicine , chemotherapy , gene
The 5‐hydroxytryptamine (serotonin, 5‐ HT ) type 3 (5‐ HT 3) receptor belongs to the superfamily of Cys‐loop ligand‐gated ion channels, and can be either homopentameric (5‐ HT 3A) or heteropentameric (5‐ HT 3 AB ) 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‐ HT 3 receptor using a two‐electrode voltage clamp technique. Topotecan inhibited 5‐ HT ‐gated current through homomeric 5‐ HT 3A receptors. Interestingly, however, additional expression of the 5‐ HT 3B subunit changed the response to topotecan dramatically from an inhibitory to a potentiatory one. This effect was dependent on the level of 5‐ HT 3B subunit expression. Moreover, the effect was reduced in the receptors containing the 5‐ HT 3B(Y129S) polymorphic variant. These finding could explain individual differences in the sensitivity to topotecan‐induced nausea and vomiting.