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首页> 外文期刊>Pharmacogenetics and genomics >Naturally occurring variants in the HTR3B gene significantly alter properties of human heteromeric 5-hydroxytryptamine-3A/B receptors.
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Naturally occurring variants in the HTR3B gene significantly alter properties of human heteromeric 5-hydroxytryptamine-3A/B receptors.

机译：HTR3B基因中天然存在的变体会显着改变人类异聚5羟基色胺3A / B受体的特性。

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OBJECTIVES: The 5-hydroxytryptamine-3 (5-HT3) receptor, a ligand-gated ion channel, is known to be involved in gut motility and peristalsis, the mediation of pain and psychiatric diseases. 5-HT3 receptor antagonists are effectively used to treat chemotherapy-induced emesis and irritable bowel syndrome. We have characterized the impact of four naturally occurring variants in the HTR3B gene leading to amino acid exchanges within the respective subunit of heteromeric 5-HT3A/B receptors on a functional and expressional level. METHODS AND RESULTS: For functional characterization, a Ca influx assay based on aequorin bioluminescence was used. Radioligand-binding studies with the 5-HT3 receptor antagonist [H]GR65630 were carried out to determine expression levels of heteromeric 5-HT3A/B receptors. Transiently transfected human embryonic kidney 293 cells using 5-HT3A and 5-HT3B complementary DNA constructs were shown to coexpress homopentameric 5-HT3A next to heteromeric 5-HT3A/B receptors. The variant p.V183I decreased surface expression, whereas p.Y129S and p.S156R led to pronounced increases of 5-HT maximum responses, despite nearly unaltered surface expression levels of heteromeric 5-HT3A/B receptors. CONCLUSION: These results may help to explain earlier reported association findings of the frequent p.Y129S and p.V183I variants with psychiatric diseases. Replication studies with larger sample pools, especially regarding the rare p.S156R variant would be useful, to obtain an idea about the predisposing role of these single nucleotide polymorphisms as susceptibility variants.
机译：目标：5-羟色胺-3（5-HT3）受体，一个配体门控离子通道，已知与肠道运动和蠕动，疼痛和精神疾病的介导有关。 5-HT3受体拮抗剂可有效用于治疗化疗引起的呕吐和肠易激综合症。我们已经表征了HTR3B基因中四个天然变异的影响，导致功能和表达水平上异源5-HT3A / B受体各自亚基内的氨基酸交换。方法和结果：为了进行功能表征，使用了基于水母发光蛋白生物发光的Ca流入试验。使用5-HT3受体拮抗剂[H] GR65630进行放射性配体结合研究，以确定5-HT3A / B异源受体的表达水平。使用5-HT3A和5-HT3B互补DNA构建体瞬时转染的人类胚胎肾293细胞已显示出与五聚体5-HT3A / B受体相邻的同五聚体5-HT3A共表达。尽管异体5-HT3A / B受体的表面表达水平几乎没有改变，但p.V183I变体降低了表面表达，而p.Y129S和p.S156R导致了5-HT最大响应的明显增加。结论：这些结果可能有助于解释先前报道的常见的p.Y129S和p.V183I变异与精神疾病的相关性。用较大的样本库进行的复制研究，尤其是有关罕见的p.S156R变体的复制研究，将有助于了解这些单核苷酸多态性作为易感性变体的易感性。

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