MRGPRX2 Activation by Rocuronium: Insights from Studies with Human Skin Mast Cells and Missense Variants.

Chalatip Chompunud Na Ayudhya,Aetas Amponnawarat,Saptarshi Roy,Hydar Ali,Carole A Oskeritzian

doi:10.3390/cells10010156

Chalatip Chompunud Na Ayudhya, Aetas Amponnawarat + Show 3 more

Open Access

https://doi.org/10.3390/cells10010156

Copy DOI

Journal: Cells	Publication Date: Jan 15, 2021
Citations: 26	License type: CC BY 4.0

Affiliation: University of Pennsylvania, University of South Carolina

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.

Highlights

Anaphylactic reactions to drugs used during general anesthesia are rare, yet seriously life-threatening conditions that can occur with a mortality rate ranging from 3% to 9% [1].Rocuronium is a widely used neuromuscular blocking drug (NMBD) that is frequently reported for perioperative hypersensitivity (POH) [2]
The goals of the present study were to determine if rocuronium causes degranulation in mouse and human mast cell (MC) and to test the hypothesis that missense mutations (M196I, L226P and L237P) in MRGPRX2’s transmembrane domains result in gain-of-function phenotype for MC degranulation by rocuronium
Attempts to demonstrate rocuronium-induced degranulation in MRGPRX2-expressing led to the idea that POH to this drug involves the activation of MRGPRX2

Summary

Introduction

Anaphylactic reactions to drugs used during general anesthesia are rare, yet seriously life-threatening conditions that can occur with a mortality rate ranging from 3% to 9% [1].Rocuronium is a widely used neuromuscular blocking drug (NMBD) that is frequently reported for perioperative hypersensitivity (POH) [2]. Some patients with rocuronium-induced POH displayed positive skin tests to irritating concentrations of rocuronium (1–10 mg/mL), despite demonstrating negative specific-IgE (sIgE) and/or basophil activation test (BAT) [4,5]. McNeil et al [3] showed that rocuronium causes intracellular Ca2+ mobilization in transfected HEK293 cells with EC50 values of 22.2 μg/mL and 261 μg/mL, for mouse MrgprB2 and human MRGPRX2, respectively. These authors showed that rocuronium induces robust degranulation in mouse PMCs via MrgprB2, its effect on human MCs was not reported [3]. High concentrations of rocuronium causes irritative skin reactions, the possibility that this is mediated via the activation of MRGPRX2 in human skin MCs has not been determined

Objectives

Methods

Discussion

Conclusion