Department of Basic and Translational Sciences, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104, USA.
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 20209, USA.
Cells. 2021 Jan 15;10(1):156. doi: 10.3390/cells10010156.
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.
先前认为，围手术期对神经肌肉阻断药物（NMBD）罗库溴铵的过敏反应（POH）是由 IgE 和肥大细胞（MC）介导的。然而，最近的一项重要观察结果表明，罗库溴铵通过 Mas 相关 G 蛋白偶联受体 B2（MrgprB2）诱导鼠腹膜 MC（PMCs）脱颗粒，这使得人们认为这种药物的 POH 涉及 MRGPRX2（MrgprB2 的人类同源物）的激活。此外，基于对一位对罗库溴铵发生 POH 的患者在 MRGPRX2 的跨膜结构域中显示出三个错义突变（M196I、L226P 和 L237P）的研究，提出这种过敏反应是由于该受体的异常激活引起的。我们发现，罗库溴铵在 20μg/mL 时通过 MrgprB2 引起鼠 PMCs 脱颗粒，但在 500μg/mL 以上时通过 MRGPRX2 诱导人 MCs 脱颗粒。此外，瞬时表达 M196I、L226P 和 L237P 变异体的 RBL-2H3 细胞在对罗库溴铵的反应中并未显示出增强的脱颗粒作用，与野生型受体相比。这些发现首次证明罗库溴铵通过 MRGPRX2 诱导人 MCs 脱颗粒。此外，MrgprB2 和 MRGPRX2 之间的重要差异以及罗库溴铵不能诱导表达 MRGPRX2 变异体的细胞增强反应的能力表明，其 POH 的机制比以前认为的更为复杂。
