Paper

TGR5-mediated Ca2+ signaling in cholangiocytes

Tordjmann, Thierry, Chen, Xuanmeng, Al-Shebel, Amr, Thibault Pebrier, Dellis, Olivier

2025

Overview

The Bile Acid TGR5 receptor is well known to active the cAMP pathways leading to CFTR activation and Cl- ions secretion, needed for bile alkalinization and hydration. However, during cystic fibrosis development, only 10 to 15% of the patients present liver defect due to bile duct disorders, meaning that another process should compensate for the loss of CFTR activity. Interestingly, TGR5 stimulation has also been reported to mobilize Ca2+ ions. Using normal human cholangiocytes and cholangiocarcinoma cell lines, we confirmed by using a specific agonist, that TGR5 stimulation induced a Ca2+ release from the endoplasmic reticulum and an influx of extracellular Ca2+ ions. Next, this Ca2+ mobilization allows an ATP (and UTP) release, leading to the activation of P2Y receptors, reinforcing this Ca2+ mobilization. This study shows that activation of the BA receptor TGR5 has the capacity to induce the two main intracellular pathways, cAMP and IP3-Ca2+ in cholangiocytes. From our data, we speculate that the pathway we described will allow activation of the Ca2+-activated Cl- channels TMEM16A, in parallel to CFTR in non-CF cells, or to compensate in part or in totality the loss of CFTR in CF patients.Competing Interest StatementThe authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Bile ducts / Calcium (extracellular) / Calcium (intracellular) / Calcium (reticular) / Calcium channels / Calcium influx / Calcium signalling / Cell lines / Chloride channels / Cholangiocarcinoma / Cyclic AMP / Cystic fibrosis / Endoplasmic reticulum / Ions / Liver diseases / Physiology