Author response: MRGPRX4 is a bile acid receptor for human cholestatic itch

Yu, Huasheng; Zhao, Tianjun; Liu, Simin; Wu, Qinxue; Johnson, Omar; Wu, Zhaofa; Zhuang, Zihao; Shi, Yao‐Cheng; Peng, Lirong; He, Renxi; Yang, Yong; Sun, Jianjun; Wang, Xiaoqun; Xu, Haifeng; Zeng, Zheng; Zou, Peng; Lei, Xiaoguang; Luo, Wenqin; Li, Yulong

doi:10.7554/elife.48431.026

Cited by 1 publication

(10 citation statements)

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“…We also verified whether LCA and DCA were chemically active. Since human MRGPRX4 can be activated by LCA and DCA (Yu et al, 2019), MRGPRX4 as a positive control was transiently expressed in HEK293T cells, and both LCA and DCA were applied. As a result, we also observed the exact same responses, as DCA and LCA both activated MRGPRX4 (Supplementary Fig.…”

Section: Lca Increases Intracellular Calcium Levels Via Mrgpra1mentioning

confidence: 99%

“…Fortunately, recent advances have elucidated the underlying mechanisms of cholestatic pruritus, emphasizing the role of bile acids in the pathogenesis of cholestatic pruritus (Sanjel and Shim, 2020). Importantly, it was recently revealed that MRGPRX4 is a bile acid receptor responsible for human cholestatic itch (Meixiong et al, 2019c;Yu et al, 2019). Deoxycholic acid (DCA) is the most potent bile acid that can activate MRGPRX4 (Meixiong et al, 2019c;Yu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, it was recently revealed that MRGPRX4 is a bile acid receptor responsible for human cholestatic itch (Meixiong et al, 2019c;Yu et al, 2019). Deoxycholic acid (DCA) is the most potent bile acid that can activate MRGPRX4 (Meixiong et al, 2019c;Yu et al, 2019). Remarkably, LCA can also marginally activate MRGPRX4, leading to a weak, albeit evident, itch sensation in humans (Yu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Deoxycholic acid (DCA) is the most potent bile acid that can activate MRGPRX4 (Meixiong et al, 2019c;Yu et al, 2019). Remarkably, LCA can also marginally activate MRGPRX4, leading to a weak, albeit evident, itch sensation in humans (Yu et al, 2019). Therefore, LCA is also a bile acid responsible for cholestatic pruritus.…”

Section: Introductionmentioning

confidence: 99%

“…Although it was previously reported that LCA activates human MRGPRX4 (Yu et al, 2019), it has not been investigated whether LCA can activate MRGPRs in mice. Therefore, in the present study, we have specifically focused on determining whether LCA can activate mouse Mrgpra1 and Mrgprb2, which are similar to MRGPRX4.…”

Section: Introductionmentioning

confidence: 99%

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Lithocholic Acid Activates Mas-Related G Protein-Coupled Receptors, Contributing to Itch in Mice

Song

Shim

2022

Biomol Ther (Seoul)

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The present study focused on lithocholic acid (LCA), a secondary bile acid that contributes to cholestatic pruritus. Although recent studies have found that LCA acts on MAS-related G protein-coupled receptor family member X4 (MRGPRX4) in humans, it is unclear which subtypes of MRGPRs are activated by LCA in mice since there is no precise ortholog of human MRGPRX4 in the mouse genome. Using calcium imaging, we found that LCA could activate mouse Mrgpra1 when transiently expressed in HEK293T cells. Moreover, LCA similarly activates mouse Mrgprb2. Importantly, LCA-induced responses showed dose-dependent effects through Mrgpra1 and Mrgprb2. Moreover, treatment with QWF (an antagonist of Mrgpra1 and Mrgprb2), YM254890 (Gαq inhibitor), and U73122 (an inhibitor of phospholipase C) significantly suppressed the LCA-induced responses, implying that the LCA-induced responses are indeed mediated by Mrgpra1 and Mrgprb2. Furthermore, LCA activated primary cultures of mouse sensory neurons and peritoneal mast cells, suggesting that Mrgpra1 and Mrgprb2 contribute to LCA-induced pruritus. However, acute injection of LCA did not induce noticeable differences in scratching behavior, implying that the pruritogenic role of LCA may be marginal in non-cholestatic conditions. In summary, the present study identified for the first time that LCA can activate Mrgpra1 and Mrgprb2. The current findings provide further insight into the similarities and differences between human and mouse MRGPR families, paving a way to understand the complex roles of these pruriceptors.

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Section: Lca Increases Intracellular Calcium Levels Via Mrgpra1mentioning

confidence: 99%