MRGPRX4 is a bile acid receptor for human cholestatic itch

Huasheng Yu,^1,2,3Tianjun Zhao,^1,2,3Simin Liu,¹Qinxue Wu,⁴Omar Johnson,⁴Zhaofa Wu,^1,2Zihao Zhuang,¹Yaocheng Shi,⁵Luxin Peng,⁵Renxi He,^1,2Yong Yang,⁶Jianjun Sun,⁷Xiaoqun Wang,⁸Haifeng Xu,⁹Zheng Zeng,¹⁰Peng Zou,⁵Xiaoguang Lei,^3,5Wenqin Luo,⁴ and  Yulong Li^1,2,3,11

Abstract

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 Ca²⁺ 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.

Research organism: Human

Supplementary Figures. https://elifesciences.org/articles/48431/figures#fig8s1