Mast cells (MCs) are immune cells that reside in tissues; particularly in the skin, and in the gastrointestinal and respiratory tracts. In recent years, there has been considerable interest in the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2), which is present on the surface of MCs and can be targeted by multiple exogenous and endogenous ligands. It is potentially implicated in non-IgE-mediated pseudoallergic reactions and inflammatory conditions such as asthma or atopic dermatitis. In this paper, we review natural products and herbal medicines that may potentially interact with MRGPRX2. They mainly belong to the classes of polyphenols, flavonoids, coumarins, and alkaloids. Representative compounds include rosmarinic acid, liquiritin from licorice extract, osthole, and sinomenine, respectively. While evidence-based medicine studies are still required, these compounds have shown diverse effects, such as antioxidant, analgesic, anti-inflammatory, or neuroprotective. However, despite potential beneficial effects, their use is also burdened with risks of fatal reactions such as anaphylaxis. The role of MRGPRX2 in these reactions is a subject of debate. This review explores the literature on xenobiotic compounds from herbal medicines that have been shown to act as MRGPRX2 ligands, and their potential clinical significance.

Background: Recent evidence indicates that the Mas-related G protein–coupled receptor X2 (MRGPRX2) can be activated by several drugs, including neuromuscular blocking agents, fluoroquinolones, and vancomycin. However, the contribution of this mechanism to drug hypersensitivity reactions (DHRs) observed in clinical practice remains incompletely understood. Single-nucleotide polymorphisms (SNPs) in the MRGPRX2 gene may alter receptor reactivity and thereby influence drug tolerance. In this study, we investigated whether selected SNPs—previously described in patients with DHRs (N62S, S313R), known but not previously tested with drugs (S325L, E164R), and predicted in silico (W248L)—affect in vitro responses to representative drug ligands. Methods: RBL-2H3 cells were transiently transfected with wild-type (WT) MRGPRX2 or its variants. Cell-surface expression of MRGPRX2 was assessed by flow cytometry. Intracellular calcium mobilization was measured after stimulation with ciprofloxacin, atracurium, and vancomycin; substance P served as a reference agonist and assay buffer as a negative control. Results: All variants exhibited comparable levels of cell-surface expression. No responses were observed in the presence of assay buffer. The S313R and S325L variants showed responses comparable to WT, with a tendency toward enhanced responses to substance P. In contrast, the E164R variant displayed a loss-of-function phenotype (p < 0.05 for all ligands vs. WT, S313R, and S325L variants), as did the in silico-predicted W248L variant (p < 0.05 for all ligands vs. WT, S313R, and S325L variants). The N62S variant demonstrated slightly reduced responses to the tested agonists compared with WT. Conclusions: Our findings indicate that under the investigated experimental conditions with ciprofloxacin, atracurium, and vancomycin: (1) N62S-transfected RBL-2H3 cells did not exhibit enhanced responses to the tested drug ligands; (2) the W248L variant exhibited the predicted loss-of-function phenotype, suggesting that in silico modeling may help assess the pathogenicity of specific MRGPRX2 variants; and (3) the remaining variants showed only partial concordance with previously published data, possibly reflecting differences in experimental design or assay conditions and highlighting the need for replication studies.

Background Neuromuscular blocking agents (NMBAs) may trigger severe perioperative hypersensitivity reactions. A recently proposed mechanism involves off-target activity of NMBAs. They are thought to directly activate the Mas-related G protein-coupled receptor X2 (MRGPRX2), leading to mast cell degranulation and drug-induced hypersensitivity reactions. This study investigated which NMBAs exert this effect, whether in silico findings are consistent with cell-based experiments, and how the affinity of NMBAs for MRGPRX2 compares with that of fluoroquinolones, known MRGPRX2 agonists. We also sought to predict MRGPRX2 binding-site mutations that might enhance interactions with these drugs. Methods Molecular docking, molecular dynamics (MD) simulations, and molecular mechanics Poisson–Boltzmann surface area binding free-energy calculations were combined with a β-hexosaminidase release assay in MRGPRX2-expressing RBL-2H3 stable cell line. Computational alanine scanning was performed to predict the impact of receptor mutations. Results We demonstrated that atracurium-induced mast cell degranulation can be attributed to its immediate metabolite, laudanosine, which binds strongly to MRGPRX2. Pipecuronium, but not rocuronium, suxamethonium, or vecuronium, exhibited high affinity for MRGPRX2 in MD simulations. Complexes of ciprofloxacin, levofloxacin, and moxifloxacin with MRGPRX2 demonstrated excellent stability in MD simulations. RBL-MX2 responses to NMBAs and fluoroquinolones were highly consistent with our MD findings. Alanine substitutions reduced the affinity of ligands for MRGPRX2. Conclusions In contrast to fluoroquinolones, NMBAs displayed different affinity for MRGPRX2. Cellular responses in bench experiments closely reflected the MD predictions. Alanine scanning revealed that the MRGPRX2 binding pocket exhibits low susceptibility to single-site mutations that enhance receptor responsiveness.