TGR5-mediated Ca²⁺ signaling in cholangiocytes

ABSTRACT

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.