Work

Plasma membrane Bile acid TGR5 receptor specific stimulation induces Ca2+ mobilisation, ATP secretion and P2Y receptors activation in cholangiocytes

Year: 2025

Type: article

Abstract: The Bile Acid receptor TGR5 is well known to activate the cAMP pathway 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 defects due to bile duct disorders, meaning that another process should compensate for the loss of CFTR activity. Interestingly, some bile acids had also been reported to mobilize Ca 2+ ions in cholangiocytes. Using normal human cholangiocytes and cholangiocarcinoma cell lines, we confirmed by using a specific agonist, that TGR5 stimulation induced a Ca 2+ release from the endoplasmic reticulum and an influx of extracellular Ca 2+ ions. Next, this Ca 2+ mobilisation allows an ATP (and UTP) release, leading to the activation of P2Y receptors, reinforcing this Ca 2+ mobilisation. This study shows that activation of the BA receptor TGR5 has the capacity to induce the two main intracellular pathways, cAMP and IP 3 -Ca 2+ in cholangiocytes. From our data, we speculate that the pathway we described will allow activation of the Ca 2+ -activated Cl − channels TMEM16A, to compensate in part or in totality the loss of CFTR in CF patients.

Source: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

DOI: 10.1016/j.bbamcr.2025.120067

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

Institutions: Inserm, Université Paris-Saclay

Language: English

Topic: Drug Transport and Resistance Mechanisms

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,930