Mas-related G protein-coupled receptor member X4 (MRGPRX4)

Mas-related G protein-coupled receptor member X4 (MRGPRX4) is a Class A GPCR selectively expressed in a subset of human dorsal root ganglion (DRG) neurons that mediate itch (pruritus). MRGPRX4 has recently been characterized as a molecular receptor for bile acids, bilirubin, and urobilin—pruritogens that accumulate in cholestatic liver disease and chronic kidney disease, causing severe, treatment-resistant itch. Functionally, MRGPRX4 couples primarily to Gq proteins with high basal activity and is modulated by other proteins such as RAMP2, which regulates its cell surface expression. Structurally, MRGPRX4 exhibits a positively charged ligand-binding pocket that facilitates the binding of negatively charged bile acids. Therapeutic strategies focus on antagonizing MRGPRX4 to alleviate cholestatic and uremic pruritus; EP547 is a notable antagonist currently in clinical development. Additionally, plasma bile acid and bilirubin levels serve as correlates or biomarkers for MRGPRX4-mediated itch. Safety considerations for MRGPRX4 antagonists include maintaining selectivity for the pruritus pathway without compromising broader sensory functions, and addressing the risk of drug-induced itch from off-target activation[1][2][3][4][5][6].

Other names

MRGPRX4MRGX4Mas-related G protein-coupled receptor X4Sensory neuron-specific G-protein coupled receptor 5/6GPCR MRGX4SNSR5SNSR6

Antagonism to block receptor activation and reduce itch (e.g., EP547 inhibits bile acid- and bilirubin-induced MRGPRX4 activation). Agonism to stimulate signaling (e.g., nateglinide acts as a potent agonist through Gq–PLC pathway).