MRGPRX2

Official Full Name

MAS related GPR family member X2

Organism

Homo sapiens

GeneID

117194

Background

Enables G protein-coupled receptor activity and neuropeptide binding activity. Involved in mast cell degranulation and positive regulation of cytokinesis. Predicted to be located in membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

MGRG3; MRGX2;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MDPTTPAWGTESTTVNGNDQALLLLCGKETLIPVFLILFIALVGLVGNGFVLWLLGFRMRRNAFSVYVLSLAGADFLFLCFQIINCLVYLSNFFCSISINFPSFFTTVMTCAYLAGLSMLSTVSTERCLSVLWPIWYRCRRPRHLSAVVCVLLWALSLLLSILEGKFCGFLFSDGDSGWCQTFDFITAAWLIFLFMVLCGSSLALLVRILCGSRGLPLTRLYLTILLTVLVFLLCGLPFGIQWFLILWIWKDSDVLFCHIHPVSVVLSSLNSSANPIIYFFVGSFRKQWRLQQPILKLALQRALQDIAEVDHSEGCFRQGTPEMSRSSLV

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Detailed Information

Mass-related G-protein coupled receptor (MRGRP) family is a large family of G protein-coupled receptors (GPCR) composed of nearly 50 members across several species among which mouse, monkey, rat, and human. MRGPRs are mainly expressed in small-diameter primary sensory neurons of the DRGs, but some members can also be found in additional highly-innervated tissues, such as cerebellum, cerebral cortex, hippocampus, uterus, testis, enteric nervous system and heart. Such a broad pattern of expression among the different MRGPRs strongly indicates specialized functions for each member of this family. Mas-related G protein-coupled receptor-X2 (MRGPRX2) is a newly discovered member of the MRGPRX family. So far, MRGPRX2 has been reported to be expressed by human skin mast cells. The MRGPRX2 is known to function as a nonselective or low-affinity binding site for the basic secretagogues, antimicrobial peptides and several other compounds, indicating that the function of MRGPRX2 is different from usual GPCRs. In 2015, McNeil et al. found that MRGPRX2 is a target for drugs associated with systemic pseudo-allergies or anaphylactic reactions.

MRGPRX2 and Mast Cell Activation

Mast cells (MC) are thought to possess a key role in the production of immediate allergic reactions, because upon activation, they release various mediators from stored granules. However, mast cells are also involved in homeostasis and inflammation, innate and adaptive immunity, as well as angiogenesis in a variety of tissues. Therefore, they are mostly found in the host-environment interface, such as the skin, gastrointestinal tract or lung, which are challenged by a variety of extrinsic agents, including allergens and pathogens. It has been shown that in response to activation by the MRGPRX2 agonist substance P (or other GPCR ligands such as C3a, C5a and endothelin-1) mast cell degranulation dynamics is rather fast leading to the immediate release of individual low-diameter secretory granules. In contrast, IgE-antigen (or IgE/anti-IgE antibody) complexes trigger a delayed and prolonged release of large and irregularly-fused mast cell granule aggregates, which are stable enough to traffic through lymphatics to reach the nearest draining lymph node. Recent studies have shown that engagement of the FcεRI pathway could lead to the release of more histamine and serotonin than observed upon engagement of the MRGPRX2 pathway.

These different mast cell activation patterns were also associated with distinct cutaneous and systemic inflammatory reactions in vivo. Notably, while intradermal injection of substance P induced a brief and locally-constrained mast cell-dependent inflammatory reaction, IgE-dependent mast cell activation was strong, lasted for a more prolonged period of time and have a systemic tendency. These experiments provided a valuable indication on the importance of deciphering by which mechanism(s) mast cells can be activated in patients to predict (and eventually block) mast cell-dependent reactions. It is tempting to speculate that mast cells could exhibit at least two different mechanisms of degranulation in human through the activation of MRGPRX2 or FcεRI, which could have very different effects on the intensity and the duration of the inflammatory reaction in vivo.

MRGPRX2 and Disease

More and more evidences show that MRGPRX2 dysregulation contributes to diseases like AD, anaphylaxis, chronic urticaria and rosacea. Therefore, the exploration of ligands, acting as agonists or antagonists (to therapeutically interfere with MRGPRX2-triggered hypersensitivity) is in full swing. Some molecules discovered as MRGPRX2 ligands could indeed be linked to MRGPRX2-triggered adverse reactions, including the “Red Man Syndrome” due to vancomycin, and injection-site erythema due to icatibant. Antagonists of MRGPRX2 have the potential to alleviate the symptoms of or to treat red man syndrome and atopic dermatitis.

Like most disease-associated structures, MRGPRX2 can be considered as a double-edged sword, which can cause disease or safeguarding health depending on the circumstances. For example, MRGPRX2 can orchestrate host-defenses and promote microbial clearance. Interestingly, the MRGPRX2 gene has undergone positive selection in human evolution, so other beneficial functions of the receptor will also be uncovered. On the other end of the spectrum are severe pseudo-allergic reactions and skin diseases. With the help of primary cells, especially from the skin, genetically modified cell lines, transgenic animals and human in vivo studies, that are only moderately invasive, it will be possible to determine if and how MRGPRX2 contributes to sensations of itch and pain, and to disorders, in which mast cells are supposedly involved, but not with type-I allergy.

References:

Karhu T, et al. Mast cell degranulation via MRGPRX2 by isolated human albumin fragments. Biochimica et Biophysica Acta (BBA)-General Subjects, 2017, 1861(11): 2530-2534.
Liu R, et al. Mast cell-mediated hypersensitivity to fluoroquinolone is MRGPRX2 dependent. International immunopharmacology, 2019, 70: 417-427.
Corbiere A, et al. MRGPRX2 sensing of cationic compounds–a bridge between nociception and skin diseases?. Experimental Dermatology, 2020.
Porebski G, et al. Mas-related G protein-coupled receptor-X2 (MRGPRX2) in drug hypersensitivity reactions. Frontiers in immunology, 2018, 9: 3027.
Wang Z, Babina M. MRGPRX2 signals its importance in cutaneous mast cell biology: Does MRGPRX2 connect mast cells and atopic dermatitis?. Experimental Dermatology, 2020.
Azimi E, Reddy V B, Lerner E A. MRGPRX2, atopic dermatitis, and red man syndrome. Itch (Philadelphia, Pa.), 2017, 2(1): e5.

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