Luminal regulation of normal and neoplastic human EC cell serotonin release is mediated by bile salts, amines, tastants, and olfactants

Abstract

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.

Wydzielanie serotoniny i melatoniny u kobiet po menopauzie z zaburzeniami odżywiania

“…main source of serotonin, and the changes of physical conditions during digestive processes stimulate its secretion [21].…”

Modeling of mammalian olfactory receptors and docking of odorants

“…Beginning in 2000, ORs have been repeatedly reported also to be expressed in non-olfactory tissues (De la Cruz et al 2009;Feldmesser et al 2006;Zhang et al 2007) where they play additional roles. Some ORs govern sperm chemotaxis (Fukuda and Touhara 2006;Spehr et al 2004), inhibit prostate cancer cell proliferation (Neuhaus et al 2009), regulate cell migration and adhesion in muscle (Griffin et al 2009), and regulate serotonin secretion of gastro-intestinal cells (Braun et al 2007;Kidd et al 2008). ORs are also reported to be tumor markers (Leja et al 2009;Weng et al 2005).…”

Artificial Sweeteners: A Systematic Review and Primer for Gastroenterologists

“…[29][30][31][32][33] Another study, however, showed no difference in CCK and GLP-1 levels in duodenal tissue between the sucralose and control groups. However, there was a significant increase in both hormone levels above controls when sucralose was combined with pea protein, suggesting that there may be a synergistic relationship between a macronutrient and sucralose to enhance incretin release.…”