Mawe Gary M, Hurd Molly, Hennig Grant W, Lavoie Brigitte
Department of Neurological Sciences, The University of Vermont, Burlington, VT, USA.
Department of Pharmacology, The University of Vermont, Burlington, VT, USA.
Adv Exp Med Biol. 2022;1383:329-334. doi: 10.1007/978-3-031-05843-1_30.
Because of their importance in the regulation of gut functions, several therapeutic targets involving serotonin-related proteins have been developed or repurposed to treat motility disorders, including serotonin transporter inhibitors, tryptophan hydroxylase blockers, 5-HT3 antagonists, and 5-HT4 agonists. This chapter focuses on our discovery of 5-HT4 receptors in the epithelial cells of the colon and our efforts to evaluate the effects of stimulating these receptors. 5-HT4 receptors appear to be expressed by all epithelial cells in the mouse colon, based on expression of a reporter gene driven by the 5-HT4 receptor promoter. Application of 5-HT4 agonists to the mucosal surface causes serotonin release from enterochromaffin cells, mucus secretion from goblet cells, and chloride secretion from enterocytes. Luminal administration of 5-HT4 agonists speeds up colonic motility and suppresses distention-induced nociceptive responses. Luminal administration of 5-HT4 agonists also decreases the development of, and improves recovery from, experimental colitis. Recent studies determined that the prokinetic actions of minimally absorbable 5-HT4 agonists are just as effective as absorbable compounds. Collectively, these findings indicate that targeting epithelial receptors with non-absorbable 5-HT4 agonists could offer a safe and effective strategy for treating constipation and colitis.
由于它们在肠道功能调节中的重要性，已经开发或重新利用了几种涉及血清素相关蛋白的治疗靶点来治疗运动障碍，包括血清素转运体抑制剂、色氨酸羟化酶阻滞剂、5-羟色胺3拮抗剂和5-羟色胺4激动剂。本章重点介绍我们在结肠上皮细胞中发现5-羟色胺4受体以及我们评估刺激这些受体的效果所做的努力。基于由5-羟色胺4受体启动子驱动的报告基因的表达，5-羟色胺4受体似乎在小鼠结肠的所有上皮细胞中都有表达。将5-羟色胺4激动剂应用于粘膜表面会导致肠嗜铬细胞释放血清素、杯状细胞分泌粘液以及肠上皮细胞分泌氯化物。向肠腔给药5-羟色胺4激动剂可加快结肠蠕动并抑制扩张诱导的伤害性反应。向肠腔给药5-羟色胺4激动剂还可减少实验性结肠炎的发生并促进其恢复。最近的研究确定，最低限度可吸收的5-羟色胺4激动剂的促动力作用与可吸收化合物一样有效。总的来说，这些发现表明，用不可吸收的5-羟色胺4激动剂靶向上皮受体可能为治疗便秘和结肠炎提供一种安全有效的策略。
