4.4 Article

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

Journal

BIOMOLECULES & THERAPEUTICS
Volume 30, Issue 1, Pages 38-47

Publisher

KOREAN SOC APPLIED PHARMACOLOGY
DOI: 10.4062/biomolther.2021.059

Keywords

Lithocholic acid; Bile acid; Pruritus; MRGPRX4; Mrgpra1; Mrgprb2

Funding

  1. National Research Foun-dation of Korea (NRF) - Korea government (MSIT) [2021R1A2C1005865]
  2. National Research Foundation of Korea [2021R1A2C1005865] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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The study identified that lithocholic acid can activate Mrgpra1 and Mrgprb2 in mice, mediating itch responses. However, the pruritogenic role of lithocholic acid may be marginal in non-cholestatic conditions.
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 (G alpha q 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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