MRGPRX2 Membrane Protein Introduction

Introduction of MRGPRX2

MRGPRX2, also known as MRGX2, MGRG3, mas-related GPR member X2, G protein-coupled receptor MRGX2, mas-related G protein-coupled receptor G3, is a 37 kDa G protein-coupled receptor (GPCR) that consists of 330 amino acids. In humans, it is encoded by the MRGPRX2 gene located on the chromosome 11p15.1. MRGPRX2 is reported to be expressed on mast cells and small-diameter neurons of the dorsal root and trigeminal ganglia. It is a primate-exclusive orphan GPCR and a member of the MRG family, a neuron-specific gene family involved in the regulation of nociception. This family is composed of about 50 members in the human, rat, mouse, macaque and rhesus monkey that can be subdivided into different subfamilies. Among them, subfamily X is specific to human, macaque and rhesus monkey, and there are four human MRGXs, including MRGPR X1, X2, X3, X4.

Function of MRGPRX2 Membrane Protein

The primate-exclusive receptor MRGPRX2 has been suggested to take part in the modulation of the pain and itch. It is a mast cell-specific receptor for basic secretagogues and also endo- or exogenous peptides containing a head group and a hydrophobic core. This protein can recognize and bind small molecular substances with a cyclized tetrahydroisoquinoline, such as non-steroidal neuromuscular blocking drugs (NMBDs) of tubocurarine and atracurium. MRGPRX2 could respond to the above compounds and mediates pseudoanaphylaxis reactions featured by inflammation, histamine release, and airway contraction. Currently, several peptides and alkaloids are discovered to activate MRGPRX2, including antibacterial protein LL-37, cortistatin-14, substance P13, PMX-53 peptide, beta-defensins, complanadine A, together with proadrenomedullin N-terminal peptide PAMP12 and at a lower extent, PAMP20. The report showed that the human mast cells express MRGPRX2, and mast cells from pluripotent stem cells, in response to LL-37 for sustained Ca²⁺ mobilization and degranulation.

Fig.1 In silico MRGPRX2 homology modeling predicts a selective agonist. (Lansu, 2017)

Application of MRGPRX2 Membrane Protein in Literature

1. Babina M., et al. Allergic FcεRI- and pseudo-allergic MRGPRX2-triggered mast cell activation routes are independent and inversely regulated by SCF. Allergy. 2018, 73(1), 256-260. PubMed ID: 28859248
   
   

   This article surprisingly found that stem cell factor (SCF) acting as the MC-supportive mediator significantly inhibited pseudo-allergic degranulation proceed by MRGPRX2, and simultaneously promoted allergic stimulation by FcεRI. They concluded that SCF had selective MC-dampening functions.

2. Hou Y., et al. Anti-pseudo-allergy effect of isoliquiritigenin is MRGPRX2-dependent. Immunol Lett. 2018, 198, 52-59. PubMed ID: 29684393
   
   

   In vitro studies in this report revealed that ISL decreased C48/80-induced calcium flux and restrained degranulation in LAD2 cells. ISL dose-dependently suppressed C48/80-induced MRGPRX2-expressing HEK293 cell activation. Their finding ISL inhibited IgE-independent allergy through the Mrgprx2 pathway displayed a new sight into pseudo-allergy and related therapy.

3. Tatemoto K., et al. Endogenous protein and enzyme fragments induce immunoglobulin E-independent activation of mast cells via a G protein-coupled receptor, MRGPRX2. Scand J Immunol. 2018, 87(5). PubMed ID: 29484687
   
   

   The review discussed the possibility that MRGPRX2 responds varieties of as-yet-unidentified ligands in vivo that had specific features, and proposed that MRGPRX2 played an essential role in regulating inflammatory reactions to endogenous harmful stimulus.

4. Alkanfari I., et al. Naturally Occurring Missense MRGPRX2 Variants Display Loss of Function Phenotype for Mast Cell Degranulation in Response to Substance P, Hemokinin-1, Human β-Defensin-3, and Icatibant. J Immunol. 2018. PubMed ID: 29794017
   
   

   The goal of the study was to confirm if nature missense variants within MRGPRX2's ECL/TM domains conduced to obtain or loss of function phenotype for mast cell (MC) degranulation when responded to neuropeptides, a host defense peptide, and a Food and Drug Administration-approved cationic drug.

5. Liu R., et al. MRGPRX2 is essential for sinomenine hydrochloride induced anaphylactoid reactions. Biochem Pharmacol. 2017, 146, 214-223. PubMed ID: 28987593
   
   

   The mast cell (MC) specific receptor MRGPRX2 triggered MC degranulation, a pivotal process in anaphylactic reactions. The results indicated the mechanism that SH-induced anaphylaxis was mediated via MRGPRX2 by activating PLC signaling pathways to provoke Ca²⁺ mobilization and degranulation of MC.

MRGPRX2 Preparation Options

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Reference

1. Lansu K, et al. (2017). In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol. 13(5), 529-536.

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