Glucagon-like peptide-1 (GLP-1) is involved in the regulation of insulin secretion and glucose homeostasis. GLP-1 release is stimulated when berberine interacts with a novel G protein family (TAS2Rs) in enteroendocrine cells. In this study, we used STC-1 cells and examined a marked increase in Ca 2+ in response to various bitter compounds. Ca 2+ responses to traditional Chinese medicine extracts, including berberine, phellodendrine and coptisine, in STC-1 cells were suppressed by the phospholipase C (PLC) inhibitor U-73122, suggesting the involvement of bitter taste receptors in changing the physiological status of enteroendocrine cells in a PLC-dependent manner. STC-1 cells showed berberine-up-regulated preproglucagon (GLP-1 precursor) mRNA and GLP-1 secretion. A QPCR analysis demonstrated that TAS2R38, a subtype of the bitter taste receptor, was associated with GLP-1 secretion. Berberine-mediated GLP-1 secretion was attenuated in response to small interfering RNA silencing of TAS2R38. The current studies demonstrated that Gα-gustducin co-localized with GLP-1 and Tas2r106 in the STC-1 cells. We further utilized inhibitors of PLC and TRPM5, which are known to participate in taste signal transduction, to investigate the underlying pathways mediated in berberine-induced GLP-1 secretion. Berberine-induced GLP-1 release from enteroendocrine cells is modulated in a PLC-dependent manner through a process involving the activation of bitter taste receptors. Together, our data demonstrated a berberine-mediated GLP-1 secretion pathway in mouse enteroendocrine cells that could be of therapeutic relevance to hyperglycemia and the role of bitter taste receptors in the function of the small intestine.

The kidney is essential in the maintenance of in vivo homeostasis by body fluid and electrolyte conservation and metabolic waste removal. Previously, we reported the expression of a novel G protein family (Tas2rs), which includes bitter taste receptors, in the kidney tubule system, including the nephrons and the collecting duct system. Bitter taste receptors could affect kidney function via Ca2+ intake. Alkaloids such as phenylthiocarbamide stimulate these receptors and cause an increase in Ca2+ intake. In this study, we determined the expression of bitter taste receptors in the immature kidney and small intestine and in primary renal epithelial cells and M-1 (collecting tubule cell line) cells, by using QPCR and immunostaining. We found no expression of bitter taste receptors in the immature kidney and small intestine several days after birth; the relative abundance of Tas2rs transcripts varied depending on the developmental stage. Tas2rs were expressed in primary renal epithelial cells and M-1 cells. The traditional Chinese medicinal plant extracts phellodendrine and coptisine caused a rapid rise in intracellular Ca2+ concentration, which was inhibited by the phospholipase C (PLC) inhibitor U-73122. Thus, phellodendrine and coptisine could change the physiological status of renal cells in vitro by mediation of bitter taste receptors in a PLC-dependent manner. Our results provide new insights on the expression and role of bitter taste receptors in renal development and function.

The small intestine is the most important digestion and absorption organ in the body. Taste receptors and taste signal transduction cascades were detected in a variety of non-lingual tissues including testis, kidney, nasal cavity, lung, heart and gastrointestinal (GI) tract. Though the expression of bitter taste receptors and taste signal transduction cascades has been reported in the gut for a decade, the evidence revealing the expression of Tas2rs in the gut remain unbelievable. Here, the amplification of 35 bitter taste receptors from small intestine cDNA revealed that all transcripts are present in duodenum, jejunum and ileum, except Tas2r117. In addition, Tas2Rs and taste-related signaling transduction cascades are also observed in mouse small intestine including duodenum, jejunum and ileum by RT-PCR and Western Blot. On the other hand, three types of transgenic system were used to investigate the expression of the bitter taste receptor Tas2r105 in mouse intestine (Tas2r105-GFP/Cre, Tas2r105-GFP/Cre-DTA and Tas2r105-GFP/Cre-LacZ). With the bitter taste receptor mTas2r105 transgenic mice, the expression of mTas2r105 is showed in the villus and crypts of small intestine. mTas2r105 positive cells are also observed at the connective tissue of villus. DTA expression in mTas2r105 + cells completely ablate the expression of mTas2r105 in intestinal epithelia, but did not ablate mTas1r3 expression in intestine epithelia. LacZ staining further reveals that bitter taste receptor mTas2r105 is expressed in crypt base cells.