Prolonged inhibition of 5-HT₃ receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization.
Prolonged inhibition of 5-HT₃ receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization.
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DOI：
10.1111/bph.12204
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发表时间：
2013-07
影响因子：
7.3
通讯作者：
Connolly CN
中科院分区：
文献类型：
--
作者：
Hothersall JD;Moffat C;Connolly CN
5-HT3受体拮抗剂帕洛诺司琼是治疗癌症期间呕吐和恶心的重要药物。其临床疗效可能与其独特的结合和清除特性以及受体下调机制有关。我们研究了帕洛诺司琼长期抑制5-HT3受体的机制，以便更好地了解其临床疗效。暴露于帕洛诺司琼后，采用[3H]格拉司琼结合和ELISA检测细胞表面受体（重组表达5HT3A或5HT3AB的COS-7细胞）。免疫荧光显微镜观察受体内吞作用。长期暴露于帕洛诺司琼可减少细胞表面[3H]格拉司琼结合位点的数量。这种下调对低温或内吞作用的药理学抑制剂（dynasty或制霉菌素）都不敏感，这表明内化没有发挥作用。我们的观察证实了这一点，细胞表面5-HT3受体水平没有变化，内吞率也没有增加。帕洛诺司琼表现出在许多小时内与受体缓慢分离，其中很大一部分结合位点被占用至少4天。此外，我们的观察表明，慢性受体下调涉及与变构结合位点的相互作用。帕洛诺司琼作为一种伪不可逆拮抗剂，由于其解离缓慢，可引起5-HT3受体的长时间抑制。不可逆绑定模式至少持续4天以上。变构受体的相互作用似乎在这一现象中起作用。
The 5-HT3 receptor antagonist palonosetron is an important treatment for emesis and nausea during cancer therapy. Its clinical efficacy may result from its unique binding and clearance characteristics and receptor down-regulation mechanisms. We investigated the mechanisms by which palonosetron exerts its long-term inhibition of 5-HT3 receptors for a better understanding of its clinical efficacy. Cell surface receptors (recombinantly expressed 5HT3A or 5HT3AB in COS-7 cells) were monitored using [3H]granisetron binding and ELISA after exposure to palonosetron. Receptor endocytosis was investigated using immunofluorescence microscopy. Chronic exposure to palonosetron reduced the number of available cell surface [3H]granisetron binding sites. This down-regulation was not sensitive to either low temperature or pharmacological inhibitors of endocytosis (dynasore or nystatin) suggesting that internalization did not play a role. This was corroborated by our observation that there was no change in cell surface 5-HT3 receptor levels or increase in endocytic rate. Palonosetron exhibited slow dissociation from the receptor over many hours, with a significant proportion of binding sites being occupied for at least 4 days. Furthermore, our observations suggest that chronic receptor down-regulation involved interactions with an allosteric binding site. Palonosetron acts as a pseudo-irreversible antagonist causing prolonged inhibition of 5-HT3 receptors due to its very slow dissociation. In addition, an irreversible binding mode persists for at least 4 days. Allosteric receptor interactions appear to play a role in this phenomenon.
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影响因子：
50.5
作者：
Aapro, M. S.;Grunberg, S. M.;Macciocchi, A.
通讯作者：
Macciocchi, A.
影响因子：
4.8
作者：
Ilegems, E;Pick, HM;Vogel, H
通讯作者：
Vogel, H
影响因子：
4.8
作者：
Cheng, Aixin;Bollan, Karen A.;Connolly, Christopher N.
通讯作者：
Connolly, Christopher N.
5-HT3受体 - 结构与功能之间的关系。
影响因子：
4.7
作者：
Barnes NM;Hales TG;Lummis SC;Peters JA
通讯作者：
Peters JA
DOI：
10.1073/pnas.0631766100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Feng, Y;Yu, S;Kirchhausen, T
通讯作者：
Kirchhausen, T