MRGPRX4 in Cholestatic Pruritus

Yu, Huasheng; Wangensteen, Kirk J.; Deng, Tao; Li, Yulong; Luo, Wenqin

doi:10.1055/s-0041-1730923

Cited by 8 publications

(14 citation statements)

References 79 publications

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“…Chronic itch is a devastating symptom and severely affects the quality of patients’ life ( Yosipovitch and Fleischer, 2003 ; Yu et al, 2021 ). Investigating the underlying mechanisms using the mouse model is important for developing novel therapies for treating chronic itch in various conditions.…”

Section: Resultsmentioning

confidence: 99%

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Scratch-AID, a deep learning-based system for automatic detection of mouse scratching behavior with high accuracy

Xiong

et al. 2022

eLife

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Mice are the most commonly used model animals for itch research and for development of anti-itch drugs. Most labs manually quantify mouse scratching behavior to assess itch intensity. This process is labor-intensive and limits large-scale genetic or drug screenings. In this study, we developed a new system, Scratch-AID Automatic Itch Detection), which could automatically identify and quantify mouse scratching behavior with high accuracy. Our system included a custom-designed videotaping box to ensure high-quality and replicable mouse behavior recording and a convolutional recurrent neural network (CRNN) trained with frame-labeled mouse scratching behavior videos, induced by nape injection of chloroquine (CQ). The best trained network achieved 97.6% recall and 96.9% precision on previously unseen test videos. Remarkably, Scratch-AID could reliably identify scratching behavior in other major mouse itch models, including the acute cheek model, the histaminergic model, and a chronic itch model. Moreover, our system detected significant differences in scratching behavior between control and mice treated with an anti-itch drug. Taken together, we have established a novel deep learning-based system that is ready to replace manual quantification for mouse scratching behavior in different itch models and for drug screening.

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Section: Resultsmentioning

confidence: 99%

“…Chronic itch affects about 13–17% of the population ( Matterne et al, 2009 ; Weisshaar and Dalgard, 2009 ), severely worsening the quality of life of affected patients. Unfortunately, treatment options for many chronic itch conditions are still limited ( Yosipovitch et al, 2018 ; Yu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Scratch-AID, a deep learning-based system for automatic detection of mouse scratching behavior with high accuracy

Xiong

et al. 2022

eLife

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“…It will be interesting to see if further studies of cholestatic itch in humans reveal physiological differences that correspond to the differences in pharmacology at the MRGPRX4 receptor. Moreover, measuring the expression of both MRGPRX4 and RAMP2 in the relevant tissues of subjects may help explain variability in the itch response data, as plasma bile levels do not correlate well with presentation of itch 1, 47, 48 . MRGPRX4 also displays a high level of single nucleotide polymorphisms (SNPs) 1, 49, 50 .…”

Section: Discussionmentioning

confidence: 99%

“…Other GPCRs are also shown to modulate itch response, including the Masrelated family members MRGPRX1 and MRGPRX2 1,50,[52][53][54] . The four MRGPRX subtypes (X1-X4) are closely related and, except for orphan MRGPRX3 for which very little is known, they all are considered itch receptors.…”

Section: Ramp2 Has Been Reported To Have Pleiotropic Effects On G Pro...mentioning

confidence: 99%

“…The four MRGPRX subtypes (X1-X4) are closely related and, except for orphan MRGPRX3 for which very little is known, they all are considered itch receptors. MRGPRX4 is most closely related to MRGPRX3 and is most distant from MRGPRX2 within the "X" branch of the MRGPR phylogeny 1 . The discovery of MRGPRX4-RAMP interactions raises the intriguing possibility that other itch receptors from the same family may also interact with the RAMPs.…”

Section: Ramp2 Has Been Reported To Have Pleiotropic Effects On G Pro...mentioning

confidence: 99%

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Itch receptor MRGPRX4 interacts with the receptor activity-modifying proteins (RAMPs)

Kotliar

Ceraudo

Kemelmakher-Liben

et al. 2022

Preprint

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Cholestatic itch is a severe and debilitating symptom in liver diseases with limited treatment options. The class A G protein-coupled receptor (GPCR) Mas-related GPCR subtype X4 (MRGPRX4) has been identified as a receptor for bile acids, which are potential cholestatic pruritogens. An increasing number of GPCRs have been shown to interact with receptor activity-modifying proteins (RAMPs), which can modulate different aspects of GPCR biology. Using a combination of multiplexed immunoassay and proximity ligation assay we show that MRGPRX4 interacts with RAMPs. The interaction of MRGPRX4 with RAMP2, but not RAMP1 or 3, causes attenuation of basal and agonist-dependent signaling, which correlates with a decrease of MRGPRX4 cell surface expression as measured using a quantitative NanoBRET pulse-chase assay. Finally, we use AlphaFold Multimer to predict the structure of the MRGPRX4-RAMP2 complex. The discovery that RAMP2 regulates MRGPRX4 may have direct implications for future drug development for cholestatic itch.

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Taurocholic acid represents an earlier and more sensitive biomarker and promotes cholestatic hepatotoxicity in ANIT‐treated rats

Yang,

Ding

et al. 2024

J of Applied Toxicology

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Bile acid homeostasis is crucial for the normal physiological functioning of the liver. Disruptions in bile acid profiles are closely linked to the occurrence of cholestatic liver injury. As part of our diagnostic and therapeutic approach, we aimed to investigate the disturbance in bile acid profiles during cholestasis and its correlation with cholestatic liver injury. Before the occurrence of liver injury, alterations in bile acid profiles were detected in both plasma and liver between 8 and 16 h, persisting up to 96 h. TCA, TCDCA, and TUDCA in the plasma, as well as TCA, TUDCA, TCDCA, TDCA, TLCA, and THDCA in the liver, emerged as early sensitive and potential markers for diagnosing ANIT‐induced cholestasis at 8–16 h. The distinguishing features of ANIT‐induced liver injury were as follows: T‐BAs exceeding G‐BAs and serum biochemical indicators surpassing free bile acids. Notably, plasma T‐BAs, particularly TCA, exhibited higher sensitivity to cholestatic hepatotoxicity compared with serum enzyme activity and liver histopathology. Further investigation revealed that TCA exacerbated ANIT‐induced liver injury by elevating liver function enzyme activity, inflammation, and bile duct proliferation and promoting the migration of bile duct epithelial cell. Nevertheless, no morphological changes or alterations in transaminase activity indicative of liver damage were observed in the rats treated with TCA alone. Additionally, there were no changes in bile acid profiles or inflammatory responses under physiological conditions with maintained bile acid homeostasis. In summary, our findings suggest that taurine‐conjugated bile acids in both plasma and liver, particularly TCA, can serve as early and sensitive markers for predicting intrahepatic cholestatic drugs and can act as potent exacerbators of cholestatic liver injury progression. However, exogenous TCA does not induce liver injury under physiological conditions where bile acid homeostasis is maintained.

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MRGPRX4 in Cholestatic Pruritus

Cited by 8 publications

References 79 publications

Scratch-AID, a deep learning-based system for automatic detection of mouse scratching behavior with high accuracy

Scratch-AID, a deep learning-based system for automatic detection of mouse scratching behavior with high accuracy

Itch receptor MRGPRX4 interacts with the receptor activity-modifying proteins (RAMPs)

Taurocholic acid represents an earlier and more sensitive biomarker and promotes cholestatic hepatotoxicity in ANIT‐treated rats

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