GPR39-mediated molecular signaling by bile acids

Area of Science:

• Biochemistry
• Cell Biology
• Gastroenterology

Background:

• Bile acids (BAs) are traditionally known for digestion.
• Emerging evidence suggests BAs also act as crucial biological signaling molecules.
• The G protein-coupled receptor GPR39's function is not fully understood.

Purpose of the Study:

• To identify the specific bile acids that activate GPR39.
• To characterize the signaling pathways downstream of GPR39 activation by bile acids.
• To validate GPR39 as a receptor for sulfated bile acids.

Main Methods:

• Intracellular calcium measurements in cultured cells and pancreatic acinar cells.
• Electrophysiologic recording in Xenopus oocytes.
• NanoBiT, ONE-GO, TANGO assays, and Ca2+ imaging were used to validate GPR39 activation.
• Analysis of Gpr39 knockout mice and mutagenesis studies.

Main Results:

• 3-O-sulfated bile acids, including lithocholic acid 3-sulfate (LCAS), taurolithocholic acid 3-sulfate (TLCAS), and glycolithocholic acid 3-sulfate (GLCAS), were identified as potent activators of GPR39.
• GPR39 activation by these sulfated BAs involved multiple Gα protein subtypes (Gαq, Gαi, and Gα12/13).
• LCAS-induced ERK1/2 phosphorylation in the pancreas and liver was significantly reduced in Gpr39 knockout mice, confirming GPR39's role in this signaling pathway.

Conclusions:

• GPR39 is a receptor for specific 3-O-sulfated bile acids.
• Sulfated bile acids trigger diverse G protein signaling cascades through GPR39.
• This study uncovers novel signaling molecules downstream of GPR39, expanding our understanding of bile acid signaling.