ArticleThe Journal of investigative dermatology2021
MRGPRX2 Is the Codeine Receptor of Human Skin Mast Cells: Desensitization through β-Arrestin and Lack of Correlation with the FcεRI Pathway.
Article in The Journal of investigative dermatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 55 citations in OpenAlex.
- Emerging Therapies for Anaphylaxis.Immunology and allergy clinics of North America · 2026Review
- Mas-Related G-Protein-Coupled Receptors: Emerging Roles in Neuropathic Pain.Biomolecules · 2026Review
- Regulation of MRGPRX2-mediated mast cell function by competence-stimulating peptide 1 and pro-adrenomedullin peptide.Frontiers in immunology · 2026Article
- Modulation of Mast Cell Activation via MRGPRX2 by Natural Oat Extract.International journal of molecular sciences · 2025Article
- Icatibant Acts as a Balanced Ligand of MRGPRX2 in Human Skin Mast Cells.Biomolecules · 2025Article
- IgE and non-IgE-mediated pathways in anaphylaxis.Seminars in immunopathology · 2025Review
- Functional heterogeneity of mast cells in cutaneous inflammation: implications for precision medicine.Frontiers in immunology · 2025Review
- Mast Cells and Mas-related G Protein-coupled Receptor X2: Itching for Novel Pathophysiological Insights to Clinical Relevance.Current allergy and asthma reports · 2024Review
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- CREB Is Critically Implicated in Skin Mast Cell Degranulation Elicited via FcεRI and MRGPRX2.Cells · 2024Article
- Article
- The MRGPR family of receptors in immunity.Immunity · 2024Review
- Mast cell degranulation and bradykinin-induced angioedema - searching for the missing link.Frontiers in immunology · 2024Review
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- Article
- Research Advances in Mast Cell Biology and Their Translation Into Novel Therapies for Anaphylaxis.The journal of allergy and clinical immunology. In practice · 2023Review
- Article
- CREB Is Activated by the SCF/KIT Axis in a Partially ERK-Dependent Manner and Orchestrates Survival and the Induction of Immediate Early Genes in Human Skin Mast Cells.International journal of molecular sciences · 2023Article
- GRK2 differentially regulates FcεRI and MRGPRB2-mediated responses in mast cells.Frontiers in immunology · 2023Article
- How "Neuronal" Are Human Skin Mast Cells?International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Codeine stimulates skin mast cells and is therefore used in skin tests and as an inducer of experimental itch. MRGPRX2 responds to various drugs, including opioids, to elicit pseudoallergic reactions, but whether it represents the main opiate receptor of skin mast cells remains unknown. By combining a number of approaches, including the silencing of MRGPRX2, we now report that MRGPRX2 is indeed the dominant codeine receptor of dermal mast cells. Activation by codeine displayed profound subject variability and correlated with secretion elicited by compound 48/80 or substance P but not by FcεRI aggregation. Degranulation by codeine was attenuated by stem cell factor, whereas the opposite was found for FcεRI. Compound 48/80 or codeine alone was 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 the Tango assay. Prestimulation with MRGPRX2 agonists (but not C3a or FcεRI 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 mast cells through 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 pseudoallergic reactions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.