GPR39-mediated molecular signaling by bile acids

Bile acids (BAs), long known for roles in food emulsion, also function as biological signals. By measuring intracellular calcium, we have recently discovered that GPR39, a G protein-coupled receptor, is a receptor for 3-O-sulfated BAs including lithocholic acid 3-sulfate (LCAS), taurolithocholic acid 3-sulfate (TLCAS) and glycolithocholic acid 3-sulfate (GLCAS) in cultured cells and in pancreatic acinar cells. We have now used multiple assays from electrophysiologic recording in Xenopus oocytes, Ca²⁺ imaging, NanoBiT, ONE-GO, and TANGO to validate GPR39 activation by BAs. Among 30 BAs, only sulfated forms (LCAS, TLCAS and GLCAS) evoked GPR39 activation, activating 9 distinct Gα protein subtypes across the Gα_q, Gα_i, and Gα_12/13 subfamilies. LCAS induced phosphorylation of ERK1/2 in the pancreas and the liver, which was markedly attenuated in Gpr39 knockout mice. Mutagenesis analysis identified the key residues essential for GPR39 signaling. Our results have revealed new signaling molecules downstream of GPR39 activation.