Naturally occurring variants in the HTR3B gene significantly alter properties of human heteromeric 5-hydroxytryptamine-3A/B receptors.

Objectives The 5-hydroxytryptamine-3 (5-HT 3 ) receptor, a ligand-gated ion channel, is known to be involved in gut motility and peristalsis, the mediation of pain and psychiatric diseases. 5-HT 3 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-HT 3A/B receptors on a functional and expressional level. Methods and results For functional characterization, a Ca 2+ influx assay based on aequorin bioluminescence was used. Radioligand-binding studies with the 5-HT 3 receptor antagonist [ 3 H]GR65630 were carried out to determine expression levels of heteromeric 5-HT 3A/B receptors. Transiently transfected human embryonic kidney 293 cells using 5-HT 3A and 5-HT 3B complementary DNA constructs were shown to coexpress homopentameric 5-HT 3A next to heteromeric 5-HT 3A/B receptors. The variant p.V1831 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.HT 3A/B receptors. Conclusion These results may help to explain earlier reported association findings of the frequent p.Y129S and p.V1831 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.