Z Gastroenterol 2021; 59(06): e62
DOI: 10.1055/s-0040-1705770
Abstract Klinik 2021

MRGPRX4 – a novel bile salt receptor expressed on sensory neurons

K Wolf
1   Department of Medicine 1 and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg
,
V Leibl
1   Department of Medicine 1 and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg
2   Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg
,
H Kühn
1   Department of Medicine 1 and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg
,
G Lisa
1   Department of Medicine 1 and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg
2   Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg
,
M Glaudo
1   Department of Medicine 1 and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg
,
MJM Fischer
3   Center for Physiology and Pharmacology, Medical University of Vienna
,
B Namer
2   Institute of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nürnberg
,
AE Kremer
1   Department of Medicine 1 and Translational Research Center, Friedrich-Alexander-University Erlangen-Nürnberg
› Author Affiliations
 

Pruritus is an agonizing symptom in various hepatobiliary disorders. Especially in cholestatic diseases, bile salt concentration is increased in bile and serum of patients. Since ileal bile acid transporters showed beneficial effects in patients suffering from cholestatic pruritus, bile salts have attracted notice as potential pruritogens. In the complex framework of molecular itch signaling, Mas gene-related G protein-coupled receptors (MRGPR) were identified as a class of ‘pruriceptors’ expressed on sensory neurons. Hence, we investigated an activation of MRGPRs by bile salts and bile of cholestatic patients. Therefore, MRG receptors were cloned and stably expressed in HEK293 cells and their activation by bile salts was measured by changes in cytosolic free calcium (Ca2+)i using ratiometric fluorimetry. Scratch activity, induced by the injection of potential pruritogens, was assessed using observer-independent, automated detection of specific scratch movements in an electric field caused by implanted magnets. In 15 healthy volunteers, the itch intensity upon intradermal or focal application of potential pruritogens was quantified on a numeric rating scale. Analyzing human bile salts on HEK cells expressing the eight human MRGPR receptors (X1, X2, X3, X4, D, E, F and G) revealed that certain bile salt species were capable to activate selectively MRGPRX4 in a dose-dependent manner. Also, bile of pruritic patients activated MRGPRX4 expressing HEK cells but not the empty vector control. Interestingly, intradermal injection of bile salts in mice did not cause scratching behavior while, in humans, focally applied or intradermally injected bile salts induced significant itch. Relevant mast-cell activation, precisely widespread axonreflex erythema, was excluded by laser-doppler imaging. Furthermore, bile salts could directly activate human neuronal cells but not murine ones, which may explain the differences between murine and human cholestasis. In a nutshell, our data suggests a novel signaling pathway for bile salt subspecies via MRGPRX4 that may contribute to cholestatic pruritus and, thus, opens up a new drug target to alleviate cholestatic pruritus.



Publication History

Article published online:
10 June 2021

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