Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.059
Lithocholic Acid Activates Mas-Related G Protein-Coupled Receptors, Contributing to Itch in Mice
Myung-Hyun Song1 and Won-Sik Shim1,2,*
1College of Pharmacy, Gachon University, Incheon 21936,
2Gachon Institute of Pharmaceutical Sciences, Incheon 21936, Republic of Korea
*E-mail: wsshim@gachon.ac.kr
Tel: +82-32-820-4960, Fax: +82-32-820-4829
Received: March 29, 2021; Revised: May 7, 2021; Accepted: June 1, 2021; Published online: July 15, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
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.
Keywords: Lithocholic acid, Bile acid, Pruritus, MRGPRX4, Mrgpra1, Mrgprb2


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