Irving Helen R, Tan Yean Y, Tochon-Danguy Nathalie, Liu Haihuang, Chetty Navinisha, Desmond Paul V, Pouton Colin W, Coupar Ian M
Department of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University, Parkville, Victoria 3052, Australia.
Life Sci. 2007 Mar 6;80(13):1198-205. doi: 10.1016/j.lfs.2006.12.025. Epub 2007 Jan 12.
Serotonin receptors are potential targets for treating functional bowel disorders. This study investigated the functional roles and expression of the 5-HT4 and the 5-HT7 receptor, which coexist in human colon circular smooth muscle. 5-HT3 receptor expression was also investigated. Part of the relaxant response to 5-HT was due to activation of 5-HT4 receptors as the apparent pKB value of the selective 5-HT4 antagonist, GR 113808, was 9.36. 5-HT4 mRNA levels were low in five tissues and undetectable in four others, but all responded to 5-HT with an EC50 value of 102.54+/-19.32 nM. The contribution of 5-HT7 receptors to the response was not readily demonstrated using the selective 5-HT7 antagonist, SB-269970, as its apparent pKB value of 7.19 (5-HT4 block with 1 microM GR 113808) was lower than the value obtained using the 5-HT7 guinea pig ileum assay (8.62). Nevertheless, the 5-HT7 receptor was expressed more consistently than the 5-HT4, but at similar levels. The 5-HT(3Ashort) and 5-HT(3B) subunits were co-expressed at similar levels, but the 5-HT(3Along) subunit was detected in only five of the nine samples tested. The findings show that 5-HT4-induced relaxation occurs at low to undetectable levels of tissue mRNA, as measured by qPCR. Although 5-HT7 receptor mRNA is detected at low, but consistent levels, the functional activity of this receptor is not readily identified given the currently available drugs.
血清素受体是治疗功能性肠道疾病的潜在靶点。本研究调查了共存于人类结肠环行平滑肌中的5-HT4和5-HT7受体的功能作用及表达情况。同时也研究了5-HT3受体的表达。对5-HT的部分舒张反应归因于5-HT4受体的激活，因为选择性5-HT4拮抗剂GR 113808的表观pKB值为9.36。5-HT4 mRNA水平在五个组织中较低，在另外四个组织中未检测到，但所有组织对5-HT的反应的EC50值为102.54±19.32 nM。使用选择性5-HT7拮抗剂SB-269970时，5-HT7受体对反应的贡献并不容易证明，因为其表观pKB值为7.19（用1 μM GR 113808阻断5-HT4）低于使用5-HT7豚鼠回肠试验得到的值（8.62）。然而，5-HT7受体的表达比5-HT4更一致，但水平相似。5-HT(3Ashort)和5-HT(3B)亚基以相似水平共表达，但5-HT(3Along)亚基仅在九个测试样本中的五个中检测到。研究结果表明，通过定量PCR测量，5-HT4诱导的舒张在组织mRNA水平低至无法检测时发生。尽管5-HT7受体mRNA在低水平但一致的水平上被检测到，但鉴于目前可用的药物，该受体的功能活性并不容易确定。
