Background-Bile acids (BAs) regulate cells by activating nuclear and membrane-bound receptors. 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.

Hydrophobic bile salts are thought to contribute to the disruption of gallbladder smooth muscle (GBSM) function that occurs in gallstone disease, but their mechanism of action is unknown. The current study was undertaken to determine how hydrophobic bile salts interact with GBSM, and how they reduce GBSM activity. The effect of hydrophobic bile salts on the activity of GBSM was measured by intracellular recording and calcium imaging using wholemount preparations from guinea pig and mouse gallbladder. RT-PCR and immunohistochemistry were used to evaluate expression of the G protein-coupled bile acid receptor, GPBAR1. Application of tauro-chenodeoxycholate (CDC, 50-100 μm) to in situ GBSM rapidly reduced spontaneous Ca 2+ flashes and action potentials, and caused a membrane hyperpolarization. Immunoreactivity and transcript for GPBAR1 were detected in gallbladder muscularis. The GPBAR1 agonist, tauro-lithocholic acid (LCA, 10 μm) mimicked the effect of CDC on GBSM. The actions of LCA were blocked by the protein kinase A (PKA) inhibitor, KT5720 (0.5-1.0 μm) and the K ATP channel blocker, glibenclamide (10 μm). Furthermore, LCA failed to disrupt GBSM activity in Gpbar1 −/− mice. The findings of this study indicate that hydrophobic bile salts activate GPBAR1 on GBSM, and this leads to activation of the cyclic AMP-PKA pathway, and ultimately the opening of K ATP channels, thus hyperpolarizing the membrane and decreasing GBSM activity. This inhibitory effect of hydrophobic bile salt activation of GPBAR1 could be a contributing factor in the manifestation of gallstone disease.

Background:The TGR5 bile acid receptor controls energy balance, inflammation, and digestion, but TGR5 signaling is poorly understood. Results: TGR5 does not interact with ␤-arrestins, internalize, or desensitize, but signals from plasma membrane rafts. Conclusion: TGR5 transmits sustained signals close to the cell surface. Significance: Understanding TGR5 signaling will facilitate design of TGR5 agonists for metabolic, inflammatory, and digestive disorders.

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