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

James Meixiong, Chirag Vasavda, Solomon H Snyder, Xinzhong Dong

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)10525-10530
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number21
DOIs
StatePublished - Jan 1 2019

Keywords

  • bile acids
  • cholestasis
  • itch
  • MRGPRX4
  • pruritus

ASJC Scopus subject areas

  • General

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