MRGPRX4 is a bile acid receptor for human cholestatic itch

• Published in: eLife Vol. 8
• Main Authors: Yu, Huasheng, Zhao, Tianjun, Liu, Simin, Wu, Qinxue, Johnson, Omar, Wu, Zhaofa, Zhuang, Zihao, Shi, Yaocheng, Peng, Luxin, He, Renxi, Yang, Yong, Sun, Jianjun, Wang, Xiaoqun, Xu, Haifeng, Zeng, Zheng, Zou, Peng, Lei, Xiaoguang, Luo, Wenqin, Li, Yulong
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 10-09-2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Acids; Agonists; Amino acids; Bile; Bile acids; Bile Acids and Salts - metabolism; Brain research; Calcium; Cell receptors; Cholestasis; chronic itch; Deoxycholic acid; Dermatologic agents; Development and progression; Dorsal root ganglia; Gallbladder diseases; Ganglia, Spinal - cytology; Ganglion cysts; Hospitals; Human subjects; Humans; Itching; Laboratories; Life sciences; Ligands; Liver; Liver diseases; Medical research; MRGPRX4; Neurons; Neuroscience; orphan GPCR; Physiological aspects; Plasma; Pruritus; Pruritus - chemically induced; Receptors, Cell Surface - metabolism; Receptors, G-Protein-Coupled - metabolism; Receptors, Histamine H4 - metabolism; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - metabolism; China; Beijing China; United States > US; bile acids; cholestasis; chronic itch; neuroscience; MRGPRX4; human; orphan GPCR
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.48431

Patients with liver diseases often suffer from chronic itch, yet the pruritogen(s) and receptor(s) remain largely elusive. Here, we identify bile acids as natural ligands for MRGPRX4. MRGPRX4 is expressed in human dorsal root ganglion (hDRG) neurons and co-expresses with itch receptor HRH1. Bile acids elicited Ca
responses in cultured hDRG neurons, and bile acids or a MRGPRX4 specific agonist induced itch in human subjects. However, a specific agonist for another bile acid receptor TGR5 failed to induce itch in human subjects and we find that human TGR5 is not expressed in hDRG neurons. Finally, we show positive correlation between cholestatic itch and plasma bile acids level in itchy patients and the elevated bile acids is sufficient to activate MRGPRX4. Taken together, our data strongly suggest that MRGPRX4 is a novel bile acid receptor that likely underlies cholestatic itch in human, providing a promising new drug target for anti-itch therapies.