MRGPRX2 is the codeine receptor of human skin mast cells: desensitization via β-arrestin and lack of correlation with the FcεRI pathway

Abstract Codeine stimulates skin mast cells (MCs) and is therefore used in skin tests and as inducer of experimental itch. MRGPRX2 responds to various drugs, including opioids, to elicit pseudo-allergic reactions, but whether it represents the main opiate receptor of skin MCs remains unknown. By combining a number of approaches, including silencing of MRGPRX2, we now report that MRGPRX2 is indeed the dominant codeine receptor of dermal MCs. Activation by codeine displayed profound subject-variability and correlated with secretion elicited by compound 48/80 (c48/80) or Substance P, but not by FceRI-aggregation. Degranulation by codeine was attenuated by SCF, while the opposite was found for FceRI. C48/80 or codeine alone were able to achieve maximum MRGPRX2 activation. MRGPRX2 was rapidly internalized on codeine binding in a β-arrestin-1-dependent manner. Codeine-triggered β-arrestin activation was also established by Tango assay. Pre-stimulation with MRGPRX2-agonists (but not C3a or FceRI-aggregation) resulted in refractoriness to further stimulation by the same or another MRGPRX2 ligand (cross-desensitization). This was duplicated in a cell line (RBL-MRGPRX2). Collectively, codeine degranulates skin MCs via MRGPRX2, at which it acts as a balanced ligand. It has yet to be determined whether codeine-induced refractoriness could be exploited to desensitize MRGPRX2 to prevent severe pseudo-allergic reactions.