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MRGPRX2 Activation by Rocuronium: Insights from Studies with Human Skin Mast Cells and Missense Variants
Chalatip Chompunud Na Ayudhya1, Aetas Amponnawarat1, Saptarshi Roy1
1Department of Basic and Translational Sciences, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA.
Abstract:
Perioperative hypersensitivity (POH) to the neuromuscular blocking drug (NMBD) rocuronium was previously thought to be IgE and mast cell (MC)-mediated. However, the recent seminal observation that rocuronium induces degranulation in murine peritoneal MCs (PMCs) via Mas-related G protein-coupled receptor B2 (MrgprB2) led to the idea that POH to this drug involves the activation of MRGPRX2 (human ortholog of MrgprB2). Furthermore, based on the demonstration that a patient with POH to rocuronium displayed three missense mutations (M196I, L226P and L237P) in MRGPRX2's transmembrane domains, it was proposed that this hypersensitivity reaction resulted from aberrant activation of this receptor. We found that rocuronium at 20 µg/mL caused degranulation in mouse PMCs via MrgprB2 but required at least 500 µg/mL to induce degranulation in human MCs via MRGPRX2. Furthermore, RBL-2H3 cells transiently expressing M196I, L226P and L237P variants did not display enhanced degranulation in response to rocuronium when compared to the wild-type receptor. These findings provide the first demonstration that rocuronium induces degranulation in human MCs via MRGPRX2. Furthermore, the important differences between MrgprB2 and MRGPRX2 and the inability of rocuronium to induce enhanced response in cells expressing MRGPRX2 variants suggest that the mechanism of its POH is more complex than previously thought.
Insights
Rocuronium causes hypersensitivity via mast cell activation, but human reactions differ from mouse models. Genetic variants in the MRGPRX2 receptor do not enhance this response, suggesting a complex mechanism for perioperative hypersensitivity.
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Perioperative hypersensitivity (POH) to rocuronium was initially attributed to IgE and mast cell (MC) pathways.
- Recent findings suggested rocuronium-induced MC degranulation in mice via MrgprB2, leading to hypotheses involving human MRGPRX2 activation.
- A patient with POH exhibited MRGPRX2 mutations, proposing aberrant receptor activation as the cause.
Purpose of the Study:
- To investigate the mechanism of rocuronium-induced degranulation in human mast cells via MRGPRX2.
- To compare rocuronium's effect on mouse MrgprB2 and human MRGPRX2.
- To assess if MRGPRX2 variants found in a hypersensitive patient alter degranulation response.
Main Methods:
- Comparing rocuronium-induced degranulation in mouse peritoneal MCs (PMCs) via MrgprB2 and human MCs via MRGPRX2.
- Utilizing RBL-2H3 cells expressing wild-type and mutated MRGPRX2 (M196I, L226P, L237P) to assess degranulation responses.
Main Results:
- Rocuronium induced PMC degranulation via MrgprB2 at 20 µg/mL.
- Human MCs required significantly higher rocuronium concentrations (≥500 µg/mL) for MRGPRX2-mediated degranulation.
- MRGPRX2 variants (M196I, L226P, L237P) did not show enhanced degranulation with rocuronium compared to wild-type.
Conclusions:
- Rocuronium induces degranulation in human MCs through MRGPRX2, but at higher concentrations than in mice.
- Significant differences exist between MrgprB2 and MRGPRX2 activation by rocuronium.
- The mechanism of rocuronium-induced POH is more complex than solely aberrant MRGPRX2 activation by variants.
