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http://purl.uniprot.org/citations/33617860http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/33617860http://www.w3.org/2000/01/rdf-schema#comment"

Background

Mas gene-related G protein-coupled receptors (MRGPRs) are a G protein-coupled receptor family responsive to various exogenous and endogenous agonists, playing a fundamental role in pain and itch sensation. The primate-specific family member MRGPRX2 and its murine orthologue MRGPRB2 are expressed by mast cells mediating IgE-independent signaling and pseudoallergic drug reactions.

Objectives

Our aim was to increase knowledge about the function and regulation of MRGPRX2/MRGPRB2, which is of major importance in prevention of drug hypersensitivity reactions and drug-induced pruritus.

Methods

To identify novel MRGPR (ant)agonists, we screened a library of pharmacologically active compounds by utilizing a high-throughput calcium mobilization assay. The identified hit compounds were analyzed for their pseudoallergic and pruritogenic effects in mice and human.

Results

We found a class of commonly used drugs activating MRGPRX2 that, to a large extent, consists of antidepressants, antiallergic drugs, and antipsychotics. Three-dimensional pharmacophore modeling revealed structural similarities of the identified agonists, classifying them as cationic amphiphilic drugs. Mast cell activation was investigated by using the 3 representatively selected antidepressants clomipramine, paroxetine, and desipramine. Indeed, we were able to show a concentration-dependent activation and MRGPRX2-dependent degranulation of the human mast cell line LAD2 (Laboratory of Allergic Diseases-2). Furthermore, clomipramine, paroxetine, and desipramine were able to induce degranulation of human skin and murine peritoneal mast cells. These substances elicited dose-dependent scratching behavior following intradermal injection into C57BL/6 mice but less so in MRGPRB2-mutant mice, as well as wheal-and-flare reactions following intradermal injections in humans.

Conclusion

Our results contribute to the characterization of structure-activity relationships and functionality of MRGPRX2 ligands and facilitate prediction of adverse reactions such as drug-induced pruritus to prevent severe drug hypersensitivity reactions."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.org/dc/terms/identifier"doi:10.1016/j.jaci.2020.12.655"xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Dong X."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Chien D."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Muller C.E."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Kuhn H."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Wolf K."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Zahn D."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Peng Q."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Metz M."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Neurath M.F."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Weigmann B."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Scheffel J."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Thimm D."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Stander S."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Agelopoulos K."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Hawro T."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Kremer A.E."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Fischer M.J.M."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Kremer A.N."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Limjunyawong N."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Glaudo M."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Boehm F."xsd:string
http://purl.uniprot.org/citations/33617860http://purl.uniprot.org/core/author"Gebhardt L."xsd:string
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