Kidd Mark, Modlin Irvin M, Gustafsson Bjorn I, Drozdov Ignat, Hauso Oyvind, Pfragner Roswitha
1Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Am J Physiol Gastrointest Liver Physiol. 2008 Aug;295(2):G260-72. doi: 10.1152/ajpgi.00056.2008. Epub 2008 Jun 12.
Mechanisms by which gut luminal content regulates secretion and motility are ill understood. We evaluated whether neuroendocrine enterochromaffin (EC) cells act as luminal sensors for a wide variety of nutrients and defined the secretory mechanisms of this process. Pure (98-99%) FACS-sorted human EC cells and neoplastic EC cells (KRJ-I) were studied. RT-PCR identified transcripts for T2R1 (bitter), OR1G1 (class II olfactory) and trace amine (TAR1) G protein-coupled receptors (GPCRs) and transporters for glutamine (SNAT1/2), glucose (GLUT1/3/SGLT1), and bile salts (ABST). Glutamine and sodium deoxycholate stimulated 5-HT release (EC(50) = 0.002-0.2 microM; 2-fold release) but were 10-100 times more potent in neoplastic EC cells, which also secreted 6-13 times more 5-HT. Tastants (caffeine, tyramine, octopamine) and olfactants (thymol and eugenol) also stimulated normal and neoplastic EC cell 5-HT secretion (EC(50) = 1.2 nM to 2.1 microM and 0.05 nM to 0.1 microM release, respectively); 2-deoxyglucose and the artificial sweetener sucralose also stimulated (EC(50) = 9.2 and 0.38 nM). 5-HT release was associated with ERK phosphorylation (1.5-fold, P < 0.02) and could be inhibited by a somatostatin analog (IC(50) = 1 pM). Eleven secretory associated genes including the vesicle docking inhibitor STXBP3 were upregulated in response to glutamine and bile salt stimulation in neoplastic EC cells. Targeting STXBP3 expression by use of antisense knockdown significantly (P < 0.05) reduced 5-HT secretion. In conclusion, EC cells express GPCRs and transporters for luminal tastants, olfactants, glutamine, glucose, and bile salts. Activation includes a panel of secretory genes, ERK phosphorylation, and 5-HT secretion. Luminal EC cell regulation is likely to be as important as G cell regulation in gastric acid secretion; development of agents to target EC cell function is therefore a critical therapeutic goal.
肠道腔内物质调节分泌和运动的机制尚未完全明了。我们评估了神经内分泌肠嗜铬（EC）细胞是否作为多种营养物质的腔内传感器，并确定了这一过程的分泌机制。研究了通过荧光激活细胞分选术（FACS）纯化的（98 - 99%）人EC细胞和肿瘤性EC细胞（KRJ - I）。逆转录聚合酶链反应（RT - PCR）鉴定出苦味受体T2R1、II类嗅觉受体OR1G1和痕量胺（TAR1）G蛋白偶联受体（GPCRs）的转录本，以及谷氨酰胺转运体（SNAT1/2）、葡萄糖转运体（GLUT1/3/SGLT1）和胆盐转运体（ABST）。谷氨酰胺和脱氧胆酸钠刺激5 - 羟色胺（5 - HT）释放（半数有效浓度（EC50） = 0.002 - 0.2微摩尔；释放量增加2倍），但在肿瘤性EC细胞中的效力要强10 - 100倍，肿瘤性EC细胞分泌的5 - HT也多6 - 13倍。味觉剂（咖啡因、酪胺、章鱼胺）和嗅觉剂（百里香酚和丁香酚）也刺激正常和肿瘤性EC细胞分泌5 - HT（EC50分别为1.2纳摩尔至2.1微摩尔和0.05纳摩尔至0.1微摩尔释放量）；2 - 脱氧葡萄糖和人工甜味剂三氯蔗糖也有刺激作用（EC50分别为9.2和0.38纳摩尔）。5 - HT释放与细胞外信号调节激酶（ERK）磷酸化相关（增加1.5倍，P < 0.02），并且可被生长抑素类似物抑制（半数抑制浓度（IC50） = 1皮摩尔）。在肿瘤性EC细胞中，包括囊泡对接抑制剂STXBP3在内的11个分泌相关基因在谷氨酰胺和胆盐刺激下上调。使用反义敲低技术靶向STXBP3表达可显著（P < 0.05）减少5 - HT分泌。总之，EC细胞表达针对腔内味觉剂、嗅觉剂、谷氨酰胺、葡萄糖和胆盐的GPCRs和转运体。激活过程包括一组分泌基因、ERK磷酸化和5 - HT分泌。腔内EC细胞调节在胃酸分泌中可能与G细胞调节同样重要；因此，开发针对EC细胞功能的药物是一个关键的治疗目标。
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