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Proc Natl Acad Sci U S A. 2019 May 21;116(21):10525-10530. doi: 10.1073/pnas.1903316116. Epub 2019 May 8.

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

Author information

1
Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
2
Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; ssnyder@jhmi.edu xdong2@jhmi.edu.
3
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
4
Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
5
Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
6
Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
7
Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.

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.

KEYWORDS:

MRGPRX4; bile acids; cholestasis; itch; pruritus

PMID:
31068464
DOI:
10.1073/pnas.1903316116

Conflict of interest statement

Conflict of interest statement: J.M. is a consultant for Escient Pharmaceuticals, a company focused on developing small molecule inhibitors for MRGPRs. X.D. is a co-founder of Escient Pharmaceuticals.

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