TY - JOUR
T1 - A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice
AU - Wolf, Katharina
AU - Kühn, Helen
AU - Boehm, Felicitas
AU - Gebhardt, Lisa
AU - Glaudo, Markus
AU - Agelopoulos, Konstantin
AU - Ständer, Sonja
AU - Ectors, Philipp
AU - Zahn, Dirk
AU - Riedel, Yvonne K.
AU - Thimm, Dominik
AU - Müller, Christa E.
AU - Kretschmann, Sascha
AU - Kremer, Anita N.
AU - Chien, Daphne
AU - Limjunyawong, Nathachit
AU - Peng, Qi
AU - Dong, Xinzhong
AU - Kolkhir, Pavel
AU - Scheffel, Jörg
AU - Søgaard, Mia Lykke
AU - Weigmann, Benno
AU - Neurath, Markus F.
AU - Hawro, Tomasz
AU - Metz, Martin
AU - Fischer, Michael J.M.
AU - Kremer, Andreas E.
N1 - Funding Information:
Financially supported by grants from the German Research Foundation to K.A. ( AG 271/1-1 , FOR2690 ), S.S.T. (STA 1159/4-1, FOR2690), and A.E.K. (KR3618/3-1, FOR2690). Additional funding was provided by the Interdisciplinary Center for Clinical Research (at the Friedrich-Alexander-University of Erlangen-Nürnberg) within grant E20 to A.E.K. and within grant E27 to A.E.K. and M.J.M.F. P.K. was supported by the Russian Academic Excellence Project 5-100 and a GA 2 LEN fellowship. K.W. was supported by a Bavarian Equal Opportunities Sponsorship (Realization Equal Opportunities for Women in Research and Teaching). C.E.M. is grateful for support by the DFG for the International Research Training Group GRK1873 , which is dedicated to research on G protein–coupled receptors.
Publisher Copyright:
© 2021 American Academy of Allergy, Asthma & Immunology
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - (drug-induced) pruritus
KW - Mas gene–related G protein–coupled receptors
KW - mast cells
KW - pseudoallergic drug reactions
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U2 - 10.1016/j.jaci.2020.12.655
DO - 10.1016/j.jaci.2020.12.655
M3 - Article
C2 - 33617860
AN - SCOPUS:85103965833
SN - 0091-6749
VL - 148
SP - 506-522.e8
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -