Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan
Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan
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DOI：
10.1111/jnc.12146
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发表时间：
2013-04-01
影响因子：
4.7
通讯作者：
Shimada, Shoichi
中科院分区：
文献类型：
--
作者：
Nakamura, Yukiko;Ishida, Yusuke;Shimada, Shoichi
5-羟色胺（5-羟色胺，5-HT）3型（5-HT 3）受体属于Cys环配体门控离子通道的超家族，并且可以是同五聚体（5-HT 3A）或异五聚体（5-HT 3AB）受体。已知几种调节剂，其抑制或增强该通道，但很少有在两种亚型之间具有任何明显的选择性或可以不同地调节一种受体。在这项研究中，我们表明，抗癌药物拓扑替康，双向调制5-HT 3受体使用双电极电压钳技术。拓扑替康通过同型5-HT 3A受体抑制5-HT门控电流。然而，有趣的是，5-HT 3B亚基的额外表达显著地改变了对拓扑替康的反应，从抑制性变为增强性。这种作用依赖于5-HT 3B亚基的表达水平。此外，在含有5-HT 3B（Y129 S）多态性变体的受体中，该作用降低。这些发现可以解释对托泊替康诱导的恶心和呕吐的敏感性的个体差异。
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.