PDF(Pubmed)
Abstract：
Disorders of gallbladder motility can lead to serious pathology. Bitter tastants acting upon bitter taste receptors (TAS2R family) have been proposed as a novel class of smooth muscle relaxants to combat excessive contraction in the airways and other organs. To explore whether this might also emerge as an option for gallbladder diseases, we here tested bitter tastants for relaxant properties and profiled Tas2r expression in the mouse gallbladder. In organ bath experiments, the bitter tastants denatonium, quinine, dextromethorphan, and noscapine, dose-dependently relaxed the pre-contracted gallbladder. Utilizing gene-deficient mouse strains, neither transient receptor potential family member 5 (TRPM5), nor the Tas2r143/Tas2r135/Tas2r126 gene cluster, nor tuft cells proved to be required for this relaxation, indicating direct action upon smooth muscle cells (SMC). Accordingly, denatonium, quinine and dextromethorphan increased intracellular calcium concentration preferentially in isolated gallbladder SMC and, again, this effect was independent of TRPM5. RT-PCR revealed transcripts of Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, and analysis of gallbladders from mice lacking tuft cells revealed preferential expression of Tas2r108 and Tas2r137 in tuft cells. A TAS2R143-mCherry reporter mouse labeled tuft cells in the gallbladder epithelium. An in silico analysis of a scRNA sequencing data set revealed Tas2r expression in only few cells of different identity, and from in situ hybridization histochemistry, which did not label distinct cells. Our findings demonstrate profound tuft cell- and TRPM5-independent relaxing effects of bitter tastants on gallbladder smooth muscle, but do not support the concept that these effects are mediated by bitter receptors.
摘要：
胆囊运动障碍可导致严重的病理。已经提出了作用于苦味受体(TAS2R家族)的苦味促味剂作为一类新型的平滑肌松弛剂来对抗气道和其他器官中的过度收缩。为了探索这是否也可能成为胆囊疾病的一种选择，我们在这里测试了促苦味剂的松弛特性和小鼠胆囊中Tas2r的异形表达。在器官浴实验中，苦味促进剂变性，奎宁,右美沙芬,和noscapine，剂量依赖性地放松了收缩前的胆囊。利用基因缺陷小鼠品系，无论是瞬时受体潜在家族成员5（TRPM5），也不是Tas2r143/Tas2r135/Tas2r126基因簇，也没有被证明是这种松弛所需要的簇细胞，指示对平滑肌细胞（SMC）的直接作用。因此，变性,奎宁和右美沙芬优先增加孤立的胆囊SMC和细胞内钙浓度，再次，这种效应与TRPM5无关.RT-PCR揭示了Tas2r108，Tas2r126，Tas2r135，Tas2r137和Tas2r143的转录本，对缺乏簇绒细胞的小鼠的胆囊的分析揭示了Tas2r108和Tas2r137在簇绒细胞中的优先表达。TAS2R143-mCherry报告小鼠标记胆囊上皮中的簇细胞。对scRNA测序数据集的计算机模拟分析显示，Tas2r仅在少数不同身份的细胞中表达，和原位杂交组织化学，它没有标记不同的细胞。我们的发现证明了苦味剂对胆囊平滑肌的深刻的簇绒细胞和TRPM5独立的放松作用，但不支持这些作用是由苦味受体介导的概念。
