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

Abstract

Patients suffering from cholestasis, the slowing or stoppage of bile flow, commonly report experiencing an intense, chronic itch. Numerous pruritogens are up-regulated in cholestatic patient sera, including bile acids (BAs). Acute injection of BAs results in itch in both mice and humans, and BA-modulating therapy is effective in controlling patient itch. Here, we present evidence that human sensory neuron-expressed Mas-related G protein-coupled receptor X4 (MRGPRX4), an orphan member of the Mrgpr family of GPCRs, is a BA receptor. Using Ca2+ imaging, we determined that pathophysiologically relevant levels of numerous BAs activated MRGPRX4. No mouse Mrgpr orthologs were activated by BAs. To assess the in vivo relevance of BA activation of MRGPRX4, we generated a humanized mouse with targeted expression of MRGPRX4 in itch-encoding sensory neurons. BAs activated MRGPRX4+ sensory neurons at higher levels compared with WT neurons. Compared with control animals, MRGPRX4+ mice scratched more upon acute injection of BAs and in a model of cholestatic itch. Overall, these data suggest that targeting MRGPRX4 is a promising strategy for alleviating cholestatic itch.

Allantoin induces pruritus by activating MrgprD in chronic kidney disease

“…In previous studies, MrgprA3, MrgprA1, MrgprC11, MrgprD and MrgprB2 in the Mrgprs family were involved in the formation of itching sensation [10, 40–42, 46–48]. Except for MrgprB2, other itch receptors of Mrgprs were only expressed on DRG neurons [39].…”

“…Mas-related G protein-coupled receptors (Mrgpr) are composed of more than 50 members, mainly expressed in the peripheral nervous system and related to sensory functions [39]. So far, the main function of Mrgprs is itch-related function and non-histamine-dependent pruritus [9, 10, 40–42]. Hence, we hypothesize that Mrgprs are probably the receptors of metabolites in the metabolic process of chronic kidney disease.…”

What are new treatment concepts in systemic itch?

“…Although total serum bile salt levels within the systemic circulation did never correlate with itch intensity and response to therapy in hepatic pruritus, certain subspecies might contribute in a yet to be determined mechanism . One mechanism might be the activation of the sub‐receptor X4 of the Mas‐related G protein‐coupled receptor family, which is expressed on sensory neurons . However, these intriguing findings in mice have to be confirmed in humans.…”

Neuropathic Itch

“…Understanding the molecular, cellular, and circuit regulation of itch sensation provides opportunities for improved therapeutics [ 81 , 82 , 83 ]. In recent years, treatment of inflammatory itch associated with atopic dermatitis, psoriasis, and prurigo nodularis has been revolutionized by identification of inflammatory molecules and receptors involved [ 19 ].…”