GPBAR-A

GPBAR-A is an agonist of bile acid receptor GPBAR1 [1].

The G protein-coupled bile acid receptor 1 (GPBAR1, TGR5) is a plasma membrane-bound receptor for bile acids. TGR5 is involved in gallstone formation and is expressed in the epithelium of human gallbladders [2].

GPBAR-A is an agonist of bile acid receptor GPBAR1. In GLUTag cells, GPBAR-A stimulated glucagon-like peptide (GLP-1) release. In primary colonic cultures, GPBAR-A increased GLP-1 release by 4.2-fold. In upper small intestinal cultures, GPBAR-A increased GLP-1 release by 2.6-fold. In GLUTag cells, GPBAR-A increased cAMP concentration by 57%. Also, GPBAR-A increased calcium in 56/149 cells and caused the mean response by 1.3-fold. In the presence of glucose, GPBAR-A increased calcium in 148/149 cells and caused the mean response by 2.6-fold. In the presence of diazoxide (the KATP channel opener, 340 μM) and 70 mM KCl, GPBAR-A also increased GLP-1 secretion. In colonic and small intestinal cultures, GPBAR-A increased the GLP-1 secretion by 2.4-fold and 1.5-fold. The GLP-1 secretion mediated by GPBAR-A was independent on KATP channel closure [1].

References:
[1].  Parker HE, Wallis K, le Roux CW, et al. Molecular mechanisms underlying bile acid-stimulated glucagon-like peptide-1 secretion. Br J Pharmacol, 2012, 165(2): 414-423.
[2].  Keitel V, Cupisti K, Ullmer C, et al. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology, 2009, 50(3): 861-870.

Molecular mechanisms underlying bile acid-stimulated glucagon-like peptide-1 secretion.[Pubmed:21718300]

Br J Pharmacol. 2012 Jan;165(2):414-23.

BACKGROUND AND PURPOSE: The glucagon-like peptides GLP-1 and GLP-2 are secreted from enteroendocrine L-cells following nutrient ingestion. Drugs that increase activity of the GLP-1 axis are highly successful therapies for type 2 diabetes, and boosting L-cell secretion is a potential strategy for future diabetes treatment. The aim of the present study was to further our understanding of the bile acid receptor GPBA (TGR5), an L-cell target currently under therapeutic exploration. EXPERIMENTAL APPROACH: GLUTag cells and mixed primary murine intestinal cultures were exposed to bile acids and a specific agonist, GPBAR-A. Secretion was measured using hormone assays and intracellular calcium and cAMP responses were monitored using real-time imaging techniques. KEY RESULTS: Bile acid-triggered GLP-1 secretion from GLUTag cells was GPBA-dependent, as demonstrated by its abolition following tgr5 siRNA transfection. Bile acids and GPBAR-A increased GLP-1 secretion from intestinal cultures, with evidence for synergy between the effects of glucose and GPBA activation. Elevation of cAMP was observed following GPBA activation in individual GLUTag cells. Direct calcium responses to GPBAR-A were small, but in the presence of the agonist, a subpopulation of cells that was previously poorly glucose-responsive exhibited robust glucose responses. In vivo, increased delivery of bile to more distal regions of the ileum augmented L-cell stimulation. CONCLUSIONS AND IMPLICATIONS: GPBA signalling in L-cells involves rapid elevation of cAMP, and enhanced calcium and secretory responses to glucose. Modulation of this receptor therapeutically may be an attractive strategy to enhance GLP-1 secretion and achieve better glycaemic control in diabetic patients.

The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders.[Pubmed:19582812]

Hepatology. 2009 Sep;50(3):861-70.

UNLABELLED: TGR5 (Gpbar-1) is a plasma membrane-bound, G protein-coupled receptor for bile acids. TGR5 messenger RNA (mRNA) has been detected in many tissues, including rat cholangiocytes and mouse gallbladder. A role for TGR5 in gallstone formation has been suggested, because TGR5 knockout mice did not develop gallstones when fed a lithogenic diet. In this study, expression and localization of TGR5 was studied in human gallbladders. TGR5 mRNA and protein were detected in all 19 gallbladders. Although TGR5 mRNA was significantly elevated in the presence of gallstones, no such relation was found for TGR5 protein levels. In order to study the localization of TGR5 in human gallbladders, a novel antibody was generated. The receptor was localized in the apical membrane and the rab11-positive recycling endosome of gallbladder epithelial cells. Furthermore, the TGR5 staining colocalized with the cyclic adenosine monophosphate-regulated chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) and the apical sodium-dependent bile salt uptake transporter, suggesting a functional coupling of TGR5 to bile acid uptake and chloride secretion. Stimulation with bile acids significantly increased cyclic adenosine monophosphate concentration in human gallbladder tissue. Incubation of gallbladder epithelial cells with a TGR5 agonist led to a rise of N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE)-fluorescence, suggestive of a decrease in intracellular chloride concentration. The TGR5 agonist-dependent increase in MQAE-fluorescence was absent in TGR5 knockout mice or in the presence of a CFTR inhibitor, indicating that TGR5 mediates chloride secretion via activation of CFTR. The presence of the receptor in both the plasma membrane and the recycling endosome indicate that TGR5 can be regulated by translocation. CONCLUSION: The data suggest a role for TGR5 in bile acid-induced fluid secretion in biliary epithelial cells.