Expression and function of the bile acid receptor GP-BAR1 (TGR5) in the murine enteric nervous system

Department of Surgery, University of California, San Francisco, CA, USA.
Neurogastroenterology and Motility (Impact Factor: 3.59). 03/2010; 22(7):814-25, e227-8. DOI: 10.1111/j.1365-2982.2010.01487.x
Source: PubMed


Bile acids (BAs) regulate cells by activating nuclear and membrane-bound receptors. G protein coupled bile acid receptor 1 (GpBAR1) is a membrane-bound G-protein-coupled receptor that can mediate the rapid, transcription-independent actions of BAs. Although BAs have well-known actions on motility and secretion, nothing is known about the localization and function of GpBAR1 in the gastrointestinal tract.
We generated an antibody to the C-terminus of human GpBAR1, and characterized the antibody by immunofluorescence and Western blotting of HEK293-GpBAR1-GFP cells. We localized GpBAR1 immunoreactivity (IR) and mRNA in the mouse intestine, and determined the mechanism by which BAs activate GpBAR1 to regulate intestinal motility.
The GpBAR1 antibody specifically detected GpBAR1-GFP at the plasma membrane of HEK293 cells, and interacted with proteins corresponding in mass to the GpBAR1-GFP fusion protein. GpBAR1-IR and mRNA were detected in enteric ganglia of the mouse stomach and small and large intestine, and in the muscularis externa and mucosa of the small intestine. Within the myenteric plexus of the intestine, GpBAR1-IR was localized to approximately 50% of all neurons and to >80% of inhibitory motor neurons and descending interneurons expressing nitric oxide synthase. Deoxycholic acid, a GpBAR1 agonist, caused a rapid and sustained inhibition of spontaneous phasic activity of isolated segments of ileum and colon by a neurogenic, cholinergic and nitrergic mechanism, and delayed gastrointestinal transit.
G protein coupled bile acid receptor 1 is unexpectedly expressed in enteric neurons. Bile acids activate GpBAR1 on inhibitory motor neurons to release nitric oxide and suppress motility, revealing a novel mechanism for the actions of BAs on intestinal motility.

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    • "In addition to hormone receptors, enteric neurones may also respond directly to absorbed nutrients and nonnutrients (Fig. 1H). They have been shown to express FFAR3, GPBAR1, and respond to glucose, amino acids, and fatty acids (Liu et al. 1999; Keely 2010; Poole et al. 2010; Soret et al. 2010; Furness et al. 2013, 2014; Nohr et al. 2013, 2015; Neunlist and Schemann 2014). "
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    ABSTRACT: Gastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein-coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux-en-Y gastric surgery. Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self-limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of the EEC system.
    08/2015; 3(4):e00155. DOI:10.1002/prp2.155
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    • "Glp1 is known to improve insulin sensitivity in both humans and mouse models of diabetes [27] [28]. GPBAR1 is also expressed in enteric nervous system and may have an effect on the afferent signal from the gut to the central nervous system [29]. Collectively, our results show a Figure 5: CETP-expressing mice on a high-fat diet display improved muscle insulin signaling and altered glucose metabolism. "
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    ABSTRACT: Cholesteryl ester transfer protein (CETP) shuttles lipids between lipoproteins, culminating in cholesteryl ester delivery to liver and increased secretion of cholesterol as bile. Since gut bile acids promote insulin sensitivity, we aimed to define if CETP improves insulin sensitivity with high-fat feeding. CETP and nontransgenic mice of both sexes became obese. Female but not male CETP mice had increased ileal bile acid levels versus nontransgenic littermates. CETP expression protected female mice from insulin resistance but had a minimal effect in males. In liver, female CETP mice showed activation of bile acid-sensitive pathways including Erk1/2 phosphorylation and Fxr and Shp gene expression. In muscle, CETP females showed increased glycolysis, increased mRNA for Dio2, and increased Akt phosphorylation, known effects of bile acid signaling. These results suggest that CETP can ameliorate insulin resistance associated with obesity in female mice, an effect that correlates with increased gut bile acids and known bile-signaling pathways.
    Molecular Metabolism 11/2013; 2(4):457-467. DOI:10.1016/j.molmet.2013.08.007
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    • "In these experiments, the protease inhibitors, PAR1 receptor antagonist also inhibited the PMCs. These data supported by Poole et al. (2010) who identified a novel mechanism for the well-known effects of BAs on intestinal motility. He found that BAs inhibit motility by a mechanism that is consistent with activation of GpBAR1 on inhibitory motor neurons that release nitric oxide (NO). "
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    ABSTRACT: The role of bile acids on the gastrointestinal motility are contradictory, especially the role of mast cells mediators in this effect. Thus, cholic acid (CA) was examined for its in vitro action on the motility of the mice colon using different doses of CA (0.3, 30, 50, 100, 200, 300 and 500 µM). The contractile activity of the colon segment was recorded as changes in intraluminal pressure under isovolumetric conditions. The mean amplitude of the peristaltic motor complexes and the frequency (interval) of phasic contractions were determined. In other experiments, to study the CA mode of action, tissues were preincubated with 5-HT3 antagonist (Granisetron hydrochloride), 5-HT4 antagonist (GR113808), H1 antagonist (Pyrilamine maleate salt) and protease activated receptor (PAR1) antagonist (BMS-200261) prior to challenge with CA (300 µM). CA inhibitory effect on contractile activity might be via its antagonistic action on the 5-HT3, 5-HT4, H1 receptors and PAR1 with variable levels. In conclusion, CA perfusion, at certain concentration levels, induced significant physiological changes in colon motility that might propose its antagonistic action on the receptors of the mast cells neuromediators.
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