MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus

Abstract

Significance Cholestatic itch is a debilitating symptom that affects hundreds of thousands of patients every year, drastically decreasing patient quality of life. Additional therapeutic targets are needed, as current therapies are ineffective for many patients. In recent years, the Mas-related G protein-coupled receptor (MRGPR) family of receptors has been linked to itch. Here, we determine that MRGPRX4 is specifically activated by numerous bile acids (BAs) up-regulated in cholestatic patient sera. To test the relevance of these findings in vivo, we generated humanized mice expressing MRGPRX4 in sensory neurons. MRGPRX4 + humanized mice display higher levels of itch in response to injection of BAs and in a mouse model of cholestasis, indicating that MRGPRX4 could play a role in cholestatic itch.