Affinage

MRGPRX2

Mas-related G-protein coupled receptor member X2 · UniProt Q96LB1

Length
330 aa
Mass
37.1 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MRGPRX2 is a promiscuous class A GPCR expressed predominantly on human skin mast cells that functions as the principal receptor for IgE-independent pseudo-allergic mast cell degranulation. It couples to both Gαi (predominant) and Gαq to activate PLC/PKC, PI3K/AKT, ERK1/2 MAPK, and STIM1-dependent store-operated Ca²⁺ entry, driving granule exocytosis, cytokine/chemokine release, and prostaglandin D₂ synthesis in response to a broad array of cationic ligands including neuropeptides (substance P, cortistatin, PAMP-12, PACAP), host defense peptides (LL-37, human β-defensin-3), opioids (morphine, codeine), neuromuscular blockers, fluoroquinolones, and the chemokine CXCL14 (PMID:35326404, PMID:28288109, PMID:38184723, PMID:12915402). Receptor desensitization is governed by β-arrestin-1-dependent internalization controlling surface abundance and β-arrestin-2-mediated signal termination, while certain ligands (AG-30/5C, icatibant) act as G protein-biased agonists that bypass β-arrestin recruitment; naturally occurring gain-of-function C-terminal variants and biased-signaling variants (Asn62Ser) further modulate pathway selectivity (PMID:35910860, PMID:30651343, PMID:33421512). MRGPRX2 expression and responsiveness are negatively regulated by SCF, IL-4, and chronic IL-33, and positively primed by acute IL-33 (via p38) and TSLP (via STAT5/JNK), while downstream exocytosis requires the DOCK2–Rac–PAK1 cytoskeletal remodeling axis and MYO1F-dependent cortical actin reorganization (PMID:28859248, PMID:30979016, PMID:33429916, PMID:36804596, PMID:33941653).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 High

    Establishing MRGPRX2 as a functional GPCR: reverse pharmacology identified cortistatin as a high-potency ligand that activates Gq-coupled Ca²⁺ mobilization without affecting cAMP, defining the receptor's initial coupling mode and ligand identity.

    Evidence Ca²⁺ mobilization and cAMP assays in MrgX2-expressing cells

    PMID:12915402

    Open questions at the time
    • Only Gq coupling demonstrated; Gi coupling not tested
    • Expression limited to DRG; mast cell expression not yet recognized
  2. 2005 High

    Revealing dual G protein coupling and ligand promiscuity: PAMP-12 was identified as a more potent agonist than cortistatin, and GTPγS binding/cAMP inhibition established that MRGPRX2 couples to both Gαq and Gαi, expanding its signaling repertoire beyond initial Gq-only reports.

    Evidence Ca²⁺ mobilization, cAMP inhibition, [³⁵S]GTPγS binding assays; SAR studies of PAMP analogs

    PMID:15823563 PMID:16111673

    Open questions at the time
    • Structural basis for how unrelated peptides share a common pharmacophore not resolved at atomic level
    • Downstream signaling cascades beyond G protein activation not mapped
  3. 2011 High

    Defining MRGPRX2 as a mast cell degranulation receptor with unusual desensitization properties: LL-37 and compound 48/80 were shown to trigger mast cell degranulation via MRGPRX2, while LL-37 uniquely resisted GRK-mediated phosphorylation, desensitization, and internalization, revealing ligand-dependent differences in receptor regulation.

    Evidence shRNA knockdown in LAD2/primary mast cells, stable transfection in RBL-2H3, GRK2/3 knockdown, Ca²⁺ and degranulation assays

    PMID:21441599 PMID:21741965 PMID:22069323

    Open questions at the time
    • Molecular basis for resistance to GRK phosphorylation not identified
    • Full spectrum of endogenous mast cell ligands unknown
  4. 2017 High

    Massively expanding the MRGPRX2 ligand repertoire and establishing receptor independence from FcεRI: high-throughput screening identified opioids, vancomycin, and δ-toxin as MRGPRX2 agonists; mutagenesis-validated homology modeling defined the binding pocket; SCF was found to selectively suppress MRGPRX2 while enhancing FcεRI responses, establishing that the two degranulation pathways are independent and inversely regulated.

    Evidence HTS of 5,695 compounds, virtual docking of ~4M compounds, mutagenesis-validated homology model, PLC pathway dissection, MrgprB2 KO mice, SCF manipulation of human skin mast cells

    PMID:28288109 PMID:28367504 PMID:28549244 PMID:28859248 PMID:28987593

    Open questions at the time
    • High-resolution experimental structure not available
    • Relative contribution of Gαi vs Gαq in primary mast cells not quantified
  5. 2018 High

    Identifying critical receptor residues and cytokine regulation: naturally occurring loss-of-function missense variants (G165E, D184H, W243R, H259Y) established shared binding sites for diverse ligands; SCF/IL-4 withdrawal experiments showed that these cytokines tonically suppress MRGPRX2 expression; LL-37 internalization was shown to require clathrin-mediated endocytosis and sialic acid.

    Evidence Systematic missense variant mutagenesis with multiple ligands, cytokine withdrawal in primary mast cells, clathrin/neuraminidase inhibitors with confocal microscopy

    PMID:29794017 PMID:30091263 PMID:30280189

    Open questions at the time
    • Structural basis for how single mutations abolish responses to structurally diverse ligands not resolved
    • Whether loss-of-function variants confer clinical protection from pseudo-allergy not tested
  6. 2019 High

    Establishing biased agonism and delineating G protein vs β-arrestin signaling: AG-30/5C and icatibant were identified as G protein-biased agonists (no β-arrestin recruitment), while compound 48/80 and substance P activate both pathways; C-terminal Ser/Thr-to-Ala substitutions produced gain-of-function, implicating C-terminal phosphorylation in desensitization; IL-33 was shown to have dual temporal regulation (acute priming via p38, chronic suppression via JNK).

    Evidence Tango β-arrestin assay, pertussis toxin/YM-254890 G protein inhibition, C-terminal mutagenesis, IL-33 time-course with kinase knockdown in primary skin mast cells

    PMID:30651343 PMID:30979016 PMID:31299111 PMID:31652731 PMID:34111449

    Open questions at the time
    • Structural determinants distinguishing balanced from biased agonists not resolved
    • Whether biased agonism translates to differential clinical outcomes unknown
  7. 2020 High

    Defining store-operated Ca²⁺ entry as essential and confirming β-arrestin-1-dependent codeine receptor identity: STIM1-dependent SOCE was shown to be required for MRGPRX2-mediated degranulation; codeine was identified as an MRGPRX2 agonist that triggers β-arrestin-1-dependent internalization and homologous desensitization; tissue heterogeneity was established as skin/synovial mast cells respond via MRGPRX2 while lung/cardiac mast cells do not.

    Evidence STIM1 genetic ablation and SOCE pharmacology in LAD2/mouse models, β-arrestin Tango assay, cross-desensitization, tissue-specific mast cell mediator profiling

    PMID:31333418 PMID:32038646 PMID:33058860

    Open questions at the time
    • Mechanism of tissue-selective MRGPRX2 expression not identified
    • Whether SOCE is the exclusive Ca²⁺ entry route or supplementary unclear
  8. 2021 High

    Mapping the cytoskeletal effector arm and separating β-arrestin isoform functions: DOCK2–Rac–PAK1 was identified as essential for granule exocytosis downstream of MRGPRX2 despite normal Ca²⁺ influx; MYO1F was shown to control cortical actin remodeling, Cdc42 activation, and mitochondrial translocation to exocytic sites; β-arrestin-1 was found to control receptor internalization while β-arrestin-2 mediates signal termination without internalization; TSLP was shown to selectively prime MRGPRX2 responses via STAT5.

    Evidence DOCK2 KO mice and inhibitors, MYO1F shRNA, β-arrestin-1/2 isoform-specific knockdown, TSLP/STAT5 RNAi in primary skin mast cells

    PMID:33429916 PMID:33941653 PMID:34070125 PMID:34329659 PMID:35910860 PMID:36804596

    Open questions at the time
    • How DOCK2–Rac and MYO1F pathways are coordinated or sequenced is unknown
    • Contribution of β-arrestin-dependent signaling to cytokine production vs degranulation not separated
  9. 2022 High

    Consolidating the signaling hierarchy and demonstrating genotype-dependent biased signaling: systematic inhibitor studies in primary skin mast cells placed Gαi upstream of ERK1/2 and AKT; a UC-protective Asn62Ser variant was shown to enhance β-arrestin recruitment while decreasing IP-1 accumulation, establishing that naturally occurring variants can bias signaling; human-selective inverse agonist C9 blocked both G protein and β-arrestin arms.

    Evidence Pertussis toxin/YM-254890 with phospho-ERK/AKT immunoblotting, variant transfection with β-arrestin/IP-1/pERK assays, C9 characterization across multiple cell systems

    PMID:33421512 PMID:35326404 PMID:36275683

    Open questions at the time
    • Cryo-EM or crystal structure of MRGPRX2 with agonist/antagonist not available
    • Whether Asn62Ser biased signaling explains UC protection mechanistically unresolved
  10. 2024 High

    Identifying CXCL14 as an endogenous chemokine agonist and demonstrating therapeutic MRGPRX2 antagonism in vivo: the C-terminal pharmacophoric sequence of CXCL14 was mapped by truncation/mutagenesis; orally administered small-molecule MRGPRX2 antagonists blocked skin mast cell degranulation in MRGPRX2 knock-in mice and human ex vivo skin microdialysis.

    Evidence CXCL14 truncation/mutagenesis with G protein and β-arrestin assays, MRGPRX2 knock-in/MrgprB2 KO mice, ex vivo human skin microdialysis

    PMID:38184723 PMID:38971540

    Open questions at the time
    • Clinical efficacy of MRGPRX2 antagonists in human pseudo-allergic disease not established
    • Full endogenous ligand landscape (additional chemokines, albumin fragments) incompletely mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the high-resolution structure of MRGPRX2 in active/inactive states, the molecular basis for how structurally diverse cationic ligands converge on common binding determinants, the mechanism controlling tissue-selective expression in skin vs lung mast cells, and whether biased agonism or genotype-dependent signaling can be exploited therapeutically.
  • No experimental atomic-resolution structure
  • Tissue-specific transcriptional regulation unexplored
  • Clinical translation of MRGPRX2 antagonism pending

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 5
Partners
ARRB1ARRB2DOCK2GNAI1GNAQMYO1FSTIM1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 MRGPRX2 (MrgX2) is a Gq-coupled GPCR that responds to cortistatin with increased intracellular Ca2+ but no effect on cAMP levels, identifying it as a high-potency cortistatin receptor expressed in dorsal root ganglia. Reverse pharmacology screening, Ca2+ mobilization assay, cAMP assay in MrgX2-expressing cells The Journal of biological chemistry High 12915402
2005 MRGPRX2 (MrgX2) is activated by proadrenomedullin N-terminal peptides (PAMP-12 > cortistatin > PAMP-20), coupling to both Gαq and Gαi, as demonstrated by Ca2+ mobilization, inhibition of forskolin-elevated cAMP, and [35S]GTPγS binding assays; the receptor is expressed in adrenal chromaffin cells and dorsal root ganglia. Ca2+ mobilization assay, cAMP inhibition assay, [35S]GTPγS binding, immunostaining Biochemical and biophysical research communications High 15823563
2005 Proadrenomedullin N-terminal peptides and cortistatin share a common structural motif for activating MrgX2, explaining how two apparently unrelated peptides activate the same receptor. Structure-activity relationship (SAR) studies of PAMP analogs in MrgX2-expressing cells European journal of pharmacology Medium 16111673
2011 MRGPRX2 (MrgX2) is a novel GPCR for the antimicrobial peptide LL-37 on human mast cells; it mediates sustained Ca2+ mobilization and degranulation, but unlike most GPCRs it is resistant to agonist-induced receptor phosphorylation, desensitization, and internalization; GRK2 and GRK3 knockdown had no effect on LL-37-induced degranulation. shRNA knockdown in LAD2 and primary CD34+ mast cells, stable transfection of MrgX2 in mast cell lines, Ca2+ mobilization and degranulation assays The Journal of biological chemistry High 22069323
2011 Compound 48/80 induces mast cell degranulation via both MrgX1 and MrgX2, whereas the C3a receptor superagonist E7 activates mast cells via MrgX2 but not MrgX1; C3a itself does not use MrgX1 or MrgX2 for degranulation. Stable transfection of MrgX1 and MrgX2 in RBL-2H3 cells, Ca2+ mobilization and degranulation assays comparing LAD2, HMC-1, and transfected RBL cells European journal of pharmacology High 21741965
2011 PMX-53 functions as both a potent CD88 antagonist and a low-affinity agonist for MrgX2 (but not MrgX1); Trp and Arg residues in PMX-53 are required for both activities. Stable transfection of MrgX1 and MrgX2 in RBL-2H3 cells, Ca2+ mobilization and degranulation assays, mutagenesis of PMX-53 (Trp→Ala and Arg→dArg substitutions) Molecular pharmacology High 21441599
2017 MRGPRX2 is activated by many opioid compounds (including morphine, hydrocodone, sinomenine, dextromethorphan, dynorphin A/B, neoendorphins) and mediates mast cell degranulation and Ca2+ release; mutagenesis-validated homology models were used to identify selective agonist ZINC-3573. High-throughput screening of 5,695 small molecules, mutagenesis-validated homology modeling, virtual docking of ~4 million compounds, functional assays in MRGPRX2-expressing cells and LAD2 mast cells Nature chemical biology High 28288109
2017 Vancomycin and staphylococcus δ-toxin evoke mast cell degranulation via MRGPRX2; a receptor antagonist inhibits this process. Mast cell degranulation assays with MRGPRX2 antagonist blockade Itch (Philadelphia, Pa.) Medium 28367504
2017 MRGPRX2-mediated sinomenine hydrochloride (SH)-induced mast cell degranulation operates through activation of PLC signaling pathways leading to Ca2+ mobilization; MrgprB2 knockout mice show reduced SH-induced inflammation, and MRGPRX2 knockdown mast cells show reduced degranulation. MrgprB2 knockout mouse model, MRGPRX2 siRNA knockdown, Ca2+ mobilization assay, hindpaw swelling/extravasation assay in vivo Biochemical pharmacology High 28987593
2017 FcεRI- and MRGPRX2-triggered mast cell degranulation pathways are completely independent and show no cross-correlation; SCF potently inhibits pseudo-allergic (MRGPRX2-mediated) degranulation while simultaneously promoting allergic (FcεRI-mediated) stimulation. Human skin mast cell degranulation assays comparing FcεRI and MRGPRX2 routes with SCF treatment, MRGPRX2 mRNA quantification Allergy Medium 28859248
2017 LL-37-induced human mast cell degranulation and IL-8 release through MrgX2 is associated with activation of Gi protein, PLC/PKC/Calcium/NFAT, PI3K/Akt, and MAPK signaling pathways; MrgX2 silencing significantly inhibits both degranulation and cytokine release. siRNA knockdown of MrgX2 in LAD2 cells, Ca2+ imaging, β-hexosaminidase release, IL-8 measurement, pathway inhibitor studies International immunopharmacology Medium 28549244
2018 Four naturally occurring missense variants in MRGPRX2's extracellular/transmembrane domains (G165E, D184H, W243R, H259Y) cause complete loss-of-function for mast cell degranulation in response to substance P, hemokinin-1, human β-defensin-3, and icatibant, suggesting these diverse ligands use common receptor sites. Stable and transient transfection of MRGPRX2 missense variants in RBL-2H3 cells, degranulation assay with multiple ligands Journal of immunology High 29794017
2018 MRGPRX2 is negatively regulated by SCF and IL-4 in skin mast cells; withdrawal of both SCF and IL-4 partially reinstates MRGPRX2 expression and pseudo-allergic responsiveness; FcεRI-triggered activation shows inverse regulation compared to MRGPRX2-mediated activation. Mast cell culture with SCF/IL-4 withdrawal, MRGPRX2 mRNA/protein quantification, functional degranulation assays Experimental dermatology Medium 30091263
2018 MrgX2-mediated LL-37 internalization occurs via clathrin-mediated endocytosis requiring sialic acid at the cell surface; LL-37 co-localizes with MrgX2 in the perinuclear region; G-protein inhibition (pertussis toxin) and MrgX2 siRNA knockdown both suppress LL-37 internalization and mast cell degranulation. siRNA knockdown of MrgX2, pertussis toxin treatment, neuraminidase treatment, clathrin endocytosis inhibitors (dynasore, chlorpromazine), confocal microscopy, β-hexosaminidase release assay in LAD2 cells Molecular medicine reports Medium 30280189
2019 Substance P (SP) induces Ca2+ mobilization and degranulation via both Gαi and Gαq family G proteins in MRGPRX2-expressing cells; conserved TM6 residue I225 and TM7 residue Y279 are essential for SP-induced responses; intracellular loop residues R138C and R141C cause loss of function; carboxyl-terminal Ser/Thr substitution (all five to Ala) and missense variants S325L and L329Q result in gain-of-function, suggesting desensitization via C-terminal phosphorylation. Pertussis toxin and YM-254890 G protein inhibition, transient transfection of MRGPRX2 variants in RBL-2H3 cells, structural modeling, Ca2+ mobilization and degranulation assays International journal of molecular sciences High 31652731
2019 AG-30/5C and icatibant are G protein-biased agonists for MRGPRX2: they induce pertussis toxin-sensitive G protein-mediated degranulation without activating β-arrestin (Tango assay); compound 48/80 signals via both G protein and β-arrestin pathways and causes MRGPRX2 internalization and subsequent desensitization; resveratrol inhibits compound 48/80-induced Tango and mast cell degranulation. shRNA silencing of MRGPRX2 in LAD2 cells, stable transfection in RBL-2H3, Tango β-arrestin assay, pertussis toxin treatment, flow cytometry for surface receptor, degranulation assay Journal of immunology High 30651343
2019 MRGPRX2 antagonists inhibit p42/44 MAPK signaling and block MRGPRX2-mediated prostaglandin D2 synthesis (de novo lipid mediator production) in human cord blood-derived mast cells; IgE- or A23187-activated mast cells are resistant to these antagonists. Novel MRGPRX2 antagonist pharmacology in human cord blood-derived mast cells, β-hexosaminidase and PGD2 assays, MAPK western blot Journal of leukocyte biology Medium 31299111
2019 IL-33 chronically reduces MRGPRX2 expression in skin mast cells via a mechanism partially requiring JNK, thereby eliminating pseudo-allergic responsiveness; in contrast, acute IL-33 priming enhances MRGPRX2-triggered degranulation through p38-dependent signaling. Chronic and acute IL-33 stimulation of human skin mast cells, Accell-mediated JNK/p38 knockdown, kinase inhibition, MRGPRX2 quantification, histamine release assay Cells High 30979016
2020 Store-operated Ca2+ entry (SOCE) via STIM1 is required for MRGPRX2-induced mast cell degranulation in vitro and MrgprB2-dependent inflammation in vivo, as shown by pharmacological and genetic ablation of STIM1. Pharmacologic SOCE inhibition and STIM1 genetic ablation in LAD2 cells, mouse peritoneal mast cells, in vivo MrgprB2-dependent models Frontiers in immunology Medium 32038646
2020 MRGPRX2 is the dominant codeine receptor in human skin mast cells; codeine binding triggers rapid MRGPRX2 internalization in a β-arrestin-1-dependent manner; prestimulation with MRGPRX2 agonists causes cross-desensitization to subsequent MRGPRX2 ligands but not to C3a or FcεRI aggregation. MRGPRX2 silencing, Tango β-arrestin assay, flow cytometry for MRGPRX2 surface expression, cross-desensitization experiments, degranulation assay in skin mast cells and RBL-MRGPRX2 cells The Journal of investigative dermatology High 33058860
2020 Morphine and substance P selectively induce histamine and tryptase (but not eicosanoid) release from human skin mast cells and synovial mast cells via MRGPRX2, but not from lung or cardiac mast cells, demonstrating heterogeneous MRGPRX2 expression and function across anatomical sites. Histamine, tryptase, PGD2, and LTC4 release assays from purified human mast cells from skin, synovium, lung, and heart Frontiers in cellular neuroscience Medium 31333418
2021 TSLP selectively cooperates with MRGPRX2 (but not FcεRI) to enhance skin mast cell granule discharge in a STAT5-dependent manner with JNK as a contributory factor; STAT5 silencing completely abolishes the priming effect. TSLP stimulation of human skin mast cells, STAT5/JNK RNA interference and pharmacological inhibition, degranulation and CD107a assays Cells High 33429916
2021 Substance P serves as a balanced agonist for MRGPRX2, inducing both G protein-mediated degranulation and β-arrestin recruitment/receptor internalization independently of G proteins; the conserved tyrosine residue Y279 in the NPxxY motif is required for both G protein- and β-arrestin-mediated responses. Tango β-arrestin assay, MRGPRX2 internalization imaging, Y279A mutagenesis in transfected RBL-2H3 cells, pertussis toxin treatment International journal of molecular sciences High 34070125
2021 DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation through Rac activation and PAK1 phosphorylation; DOCK2-deficient mast cells show impaired Rac activation and PAK1 phosphorylation downstream of MRGPRB2 despite normal calcium influx and proximal signaling. DOCK2-deficient mice, genetic inactivation in human/murine mast cells, small-molecule DOCK2 inhibitors, Rac activation assay, PAK1 phosphorylation western blot, in vivo anaphylaxis models The Journal of allergy and clinical immunology High 36804596
2021 Both β-arrestin-1 and β-arrestin-2 restrain MRGPRX2-triggered degranulation and ERK1/2 activation in human skin mast cells: β-arrestin-1 controls MRGPRX2 surface abundance (internalization), while β-arrestin-2 mediates signal termination without receptor internalization. RNA interference of β-arrestin-1 and β-arrestin-2 in human skin mast cells, MRGPRX2 surface expression quantification, ERK1/2 and AKT phosphorylation, degranulation assays with three MRGPRX2 agonists Frontiers in allergy High 35910860
2022 MRGPRX2-mediated degranulation in human skin mast cells requires Gαi (more prominent) and Gαq G proteins, Ca2+ channels, PI3K, and ERK1/2; Gαi inhibition also reduces pERK1/2 and pAKT, placing Gαi upstream of these kinase cascades. Pertussis toxin (Gαi inhibition), YM-254890 (Gαq inhibition), Ca2+ channel blockers, PI3K/ERK/JNK inhibitors, immunoblotting for phosphorylation events in purified primary human skin mast cells Cells High 35326404
2022 The inverse MRGPRX2 agonist C9 inhibits both G protein-mediated degranulation and β-arrestin recruitment/MRGPRX2 internalization in response to SP, PAMP-12, and rocuronium, but has no effect on C3a, FcεRI-mediated responses, or MrgprB2 in mouse mast cells, demonstrating specificity for human MRGPRX2. Stable MRGPRX2-expressing RBL-2H3 cells, LAD2 cells, primary human skin mast cells, β-arrestin recruitment assay, CD63/CD107a flow cytometry, β-hexosaminidase assay, pertussis toxin treatment in mouse peritoneal mast cells Frontiers in immunology High 36275683
2021 MrgprB2-mediated MRGPRX2 activation drives tryptase release from mast cells, and tryptase is involved in the release of type 2 cytokines contributing to inflammatory development in atopic dermatitis; MrgprB2 conditional knockout mice show milder AD phenotypes. MrgprB2 conditional KO mouse model with MC903-induced AD, tryptase antagonist treatment, cytokine and IgE correlation analysis The Journal of investigative dermatology Medium 37482287
2021 MRGPRX2 cytokine induction (TNF-α, IL-8, IL-13, CCL1, CCL2) in skin mast cells is ERK1/2-dependent; rapid and durable ERK1/2 phosphorylation follows MRGPRX2 ligation; PI3K and JNK have variable contributions; cytokine profiles from MRGPRX2 and FcεRI activation are similar but MRGPRX2 is less potent. MRGPRX2 agonist (compound 48/80, substance P) stimulation of human skin mast cells, MEK/ERK inhibitors, PI3K/JNK/p38 inhibitors, mRNA/protein cytokine quantification, ERK1/2 phosphorylation immunoblot The Journal of investigative dermatology Medium 34329659
2021 MYO1F (unconventional myosin) is required for full MRGPRX2-mediated mast cell degranulation; MYO1F knockdown reduces cortical actin ring reassembly after activation, Cdc42 GTPase activation, granule membrane localization, and mitochondria translocation to exocytic sites, with reduced AKT and DRP1 phosphorylation. shRNA knockdown of MYO1F in human mast cells, cortical actin imaging, Cdc42 activation assay, granule/mitochondria localization microscopy, AKT/DRP1 phosphorylation western blot, degranulation assay Journal of immunology Medium 33941653
2023 MRGPRX2 is activated by PACAP in a dose-dependent manner on human mast cells; meningeal MrgprB2-expressing mast cells contribute to PACAP-induced migraine-like pain behavior in mice, and MRGPRX2 transgenic mice show increased PACAP-induced migraine-like pain vs receptor-absent controls. MRGPRX2 transgenic mouse model, mast cell enzyme release assay, behavioral migraine pain assay Scientific reports Medium 37516794
2022 The downstream signaling of MRGPRX2 involves PLCγ/PI3K/AKT and ERK1/2 pathways; authentic MRGPRX2 in LAD2 cells and ectopically expressed MRGPRX2 in RBL-2H3 cells share similar dose-response, kinetics, and signaling including ERK1/2 MAPK, PLC, and autophagy-related signaling; underlying mechanisms differ from those of rodent MrgprB2 orthologs. Comparative pharmacological profiling (signaling inhibitors) of LAD2 and RBL-MRGPRX2 cells with compound 48/80, substance P, and vancomycin; ERK1/2, PLC, autophagy inhibitors; degranulation assays Cells Medium 33673037
2021 MRGPRX2 signals via PLCγ–IP3R-related Ca2+ fluctuations downstream of PI3K/AKT pathway; MrgprX2 knockdown in LAD2 cells reduces C48/80-induced calcium flux and downstream cytokine/chemokine release; p-AKT and PLCγ are upregulated upon MrgprX2 activation and downregulated upon knockdown. MrgprX2 siRNA knockdown in LAD2 cells, PI3K/PLCγ inhibitors, intracellular Ca2+ imaging, β-hexosaminidase assay, western blot for p-AKT and PLCγ International immunopharmacology Medium 34920312
2024 The chemokine CXCL14 potently and selectively activates MRGPRX2 and MrgprB2 through both G protein-dependent and β-arrestin recruitment pathways; truncation and mutagenesis identified the C-terminal 4-11 amino acid pharmacophoric sequence of CXCL14 responsible for receptor activation. GPCR panel screening, G protein and β-arrestin functional assays, truncation and mutagenesis of CXCL14, selective MRGPRX2/B2 antagonist blockade, computational docking Communications biology High 38184723
2024 Small molecule MRGPRX2 antagonists potently inhibit agonist-induced mast cell degranulation in vitro (LAD2, stem cell-derived, and isolated skin mast cells), in vivo (MRGPRX2 knock-in mice, Mrgprb2 KO controls), and ex vivo (human skin microdialysis), demonstrating that orally administered MRGPRX2 antagonism blocks skin mast cell degranulation. Multiple mast cell functional assays, MRGPRX2 knock-in transgenic mice, Mrgprb2 KO mice, skin vascular permeability assay, human skin ex vivo microdialysis The Journal of allergy and clinical immunology High 38971540
2019 The P17 ant venom peptide activates MRGPRX2 in a dose-dependent manner; residue Lys8 of P17 forms a cation-π interaction with Phe172 of MRGPRX2, demonstrated by mutagenesis ([Ala8]P17 loses activity); MRGPRX2-activated mast cells recruit and differentiate monocytes via chemokine release. GPCR screening of 314 receptors, β-arrestin recruitment assay, in silico docking and in vitro mutagenesis, β-hexosaminidase/cytokine assays, MRGPRX2 shRNA knockdown, monocyte migration/differentiation assays The Journal of allergy and clinical immunology High 34111449
2020 Osthole inhibits MRGPRX2-induced mast cell Ca2+ mobilization, degranulation, and chemokine/cytokine production; molecular docking suggests allosteric binding rather than competition at the orthosteric site; osthole reduces both surface and intracellular MRGPRX2 expression. Ca2+ mobilization assay, degranulation assay in LAD2 cells, in vivo MrgprB2-dependent mouse models, molecular docking, flow cytometry and confocal microscopy for MRGPRX2 expression Frontiers in immunology Medium 32391014
2022 A UC-protective MRGPRX2 variant (Asn62Ser) enhances β-arrestin recruitment, decreases IP-1 accumulation, and increases phosphorylated ERK (pERK) in response to MRGPRX2 agonists, demonstrating genotype-dependent biased signaling; adrenomedullin (processed to PAMP-12 agonist) is produced by activated fibroblasts and epithelial cells in inflamed UC regions. Variant transfection into CHO and HMC 1.1 cells, β-arrestin recruitment assay, IP-1 accumulation assay, pERK measurement; single-cell RNA sequencing for cellular source of adrenomedullin Gastroenterology Medium 33421512

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nature chemical biology 234 28288109
2003 MrgX2 is a high potency cortistatin receptor expressed in dorsal root ganglion. The Journal of biological chemistry 204 12915402
2011 Mas-related gene X2 (MrgX2) is a novel G protein-coupled receptor for the antimicrobial peptide LL-37 in human mast cells: resistance to receptor phosphorylation, desensitization, and internalization. The Journal of biological chemistry 199 22069323
2018 Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2) in Drug Hypersensitivity Reactions. Frontiers in immunology 138 30619367
2021 Multifaceted MRGPRX2: New insight into the role of mast cells in health and disease. The Journal of allergy and clinical immunology 136 33957166
2018 MRGPRX2-mediated mast cell response to drugs used in perioperative procedures and anaesthesia. Scientific reports 122 30072729
2011 G protein coupled receptor specificity for C3a and compound 48/80-induced degranulation in human mast cells: roles of Mas-related genes MrgX1 and MrgX2. European journal of pharmacology 94 21741965
2005 Identification of MrgX2 as a human G-protein-coupled receptor for proadrenomedullin N-terminal peptides. Biochemical and biophysical research communications 90 15823563
2021 MRGPRX2 and Adverse Drug Reactions. Frontiers in immunology 87 34421893
2019 Heterogeneity of Human Mast Cells With Respect to MRGPRX2 Receptor Expression and Function. Frontiers in cellular neuroscience 86 31333418
2020 The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function. Allergy 85 32003863
2021 Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2). Cells 81 33925682
2017 Brief communication: MRGPRX2, atopic dermatitis and red man syndrome. Itch (Philadelphia, Pa.) 80 28367504
2021 Inflamed Ulcerative Colitis Regions Associated With MRGPRX2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target. Gastroenterology 77 33421512
2017 Allergic FcεRI- and pseudo-allergic MRGPRX2-triggered mast cell activation routes are independent and inversely regulated by SCF. Allergy 74 28859248
2020 MRGPRX2 Activation Causes Increased Skin Reactivity in Patients with Chronic Spontaneous Urticaria. The Journal of investigative dermatology 73 32771471
2018 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. Journal of immunology (Baltimore, Md. : 1950) 71 29794017
2011 PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Molecular pharmacology 69 21441599
2021 Mast Cell-Specific MRGPRX2: a Key Modulator of Neuro-Immune Interaction in Allergic Diseases. Current allergy and asthma reports 68 33398613
2017 MRGPRX2 is essential for sinomenine hydrochloride induced anaphylactoid reactions. Biochemical pharmacology 64 28987593
2021 Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells. Cells 63 34831128
2020 Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses. Frontiers in immunology 63 32391014
2018 Quercetin inhibits Mrgprx2-induced pseudo-allergic reaction via PLCγ-IP3R related Ca2+ fluctuations. International immunopharmacology 62 30471617
2019 Identification of Gain and Loss of Function Missense Variants in MRGPRX2's Transmembrane and Intracellular Domains for Mast Cell Activation by Substance P. International journal of molecular sciences 61 31652731
2017 Saikosaponin A inhibits compound 48/80-induced pseudo-allergy via the Mrgprx2 pathway in vitro and in vivo. Biochemical pharmacology 61 29274317
2017 Typical antimicrobials induce mast cell degranulation and anaphylactoid reactions via MRGPRX2 and its murine homologue MRGPRB2. European journal of immunology 58 28688196
2020 MRGPRX2 signals its importance in cutaneous mast cell biology: Does MRGPRX2 connect mast cells and atopic dermatitis? Experimental dermatology 57 32866307
2020 Imperatorin ameliorates mast cell-mediated allergic airway inflammation by inhibiting MRGPRX2 and CamKII/ERK signaling pathway. Biochemical pharmacology 56 33387483
2019 Novel MRGPRX2 antagonists inhibit IgE-independent activation of human umbilical cord blood-derived mast cells. Journal of leukocyte biology 56 31299111
2022 Mast cells, cortistatin, and its receptor, MRGPRX2, are linked to the pathogenesis of chronic prurigo. The Journal of allergy and clinical immunology 48 35283140
2019 IL-33 and MRGPRX2-Triggered Activation of Human Skin Mast Cells-Elimination of Receptor Expression on Chronic Exposure, but Reinforced Degranulation on Acute Priming. Cells 48 30979016
2017 LL-37-induced human mast cell activation through G protein-coupled receptor MrgX2. International immunopharmacology 48 28549244
2019 MrgX2 is a promiscuous receptor for basic peptides causing mast cell pseudo-allergic and anaphylactoid reactions. Pharmacology research & perspectives 47 31832205
2020 MRGPRX2 Is the Codeine Receptor of Human Skin Mast Cells: Desensitization through β-Arrestin and Lack of Correlation with the FcεRI Pathway. The Journal of investigative dermatology 46 33058860
2024 Inhibition of mast cell degranulation by novel small molecule MRGPRX2 antagonists. The Journal of allergy and clinical immunology 45 38971540
2021 A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice. The Journal of allergy and clinical immunology 45 33617860
2021 Cytokines Stimulated by IL-33 in Human Skin Mast Cells: Involvement of NF-κB and p38 at Distinct Levels and Potent Co-Operation with FcεRI and MRGPRX2. International journal of molecular sciences 45 33808264
2021 Novel Insights on MRGPRX2-Mediated Hypersensitivity to Neuromuscular Blocking Agents And Fluoroquinolones. Frontiers in immunology 45 34385999
2023 Mast Cells Initiate Type 2 Inflammation through Tryptase Released by MRGPRX2/MRGPRB2 Activation in Atopic Dermatitis. The Journal of investigative dermatology 44 37482287
2020 Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions. Frontiers in immunology 43 32038646
2021 Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK. Cells 41 33429916
2019 Angiogenic Host Defense Peptide AG-30/5C and Bradykinin B2 Receptor Antagonist Icatibant Are G Protein Biased Agonists for MRGPRX2 in Mast Cells. Journal of immunology (Baltimore, Md. : 1950) 41 30651343
2021 Elevated MRGPRX2 Levels Related to Disease Severity in Patients With Chronic Spontaneous Urticaria. Allergy, asthma & immunology research 40 33733642
2019 Mast cell-mediated hypersensitivity to fluoroquinolone is MRGPRX2 dependent. International immunopharmacology 40 30856392
2005 Expression of cortistatin and MrgX2, a specific cortistatin receptor, in human neuroendocrine tissues and related tumours. The Journal of pathology 40 16161007
2018 Cisatracurium induces mast cell activation and pseudo-allergic reactions via MRGPRX2. International immunopharmacology 39 30032049
2018 MRGPRX2 is negatively targeted by SCF and IL-4 to diminish pseudo-allergic stimulation of skin mast cells in culture. Experimental dermatology 38 30091263
2021 MRGPRX2 Activation by Rocuronium: Insights from Studies with Human Skin Mast Cells and Missense Variants. Cells 36 33467419
2020 A novel MRGPRX2-targeting antagonistic DNA aptamer inhibits histamine release and prevents mast cell-mediated anaphylaxis. European journal of pharmacology 36 32320700
2020 MRGPRX2 and Immediate Drug Hypersensitivity: Insights From Cultured Human Mast Cells. Journal of investigational allergology & clinical immunology 36 32732181
2022 MRGPRX2-Mediated Degranulation of Human Skin Mast Cells Requires the Operation of Gαi, Gαq, Ca++ Channels, ERK1/2 and PI3K-Interconnection between Early and Late Signaling. Cells 35 35326404
2022 Novel small molecule MRGPRX2 antagonists inhibit a murine model of allergic reaction. The Journal of allergy and clinical immunology 35 36581009
2020 MRGPRX2 sensing of cationic compounds-A bridge between nociception and skin diseases? Experimental dermatology 35 33107136
2022 Inhibition of MRGPRX2 but not FcεRI or MrgprB2-mediated mast cell degranulation by a small molecule inverse receptor agonist. Frontiers in immunology 34 36275683
2021 Substance P Serves as a Balanced Agonist for MRGPRX2 and a Single Tyrosine Residue Is Required for β-Arrestin Recruitment and Receptor Internalization. International journal of molecular sciences 34 34070125
2020 Roles of a Mast Cell-Specific Receptor MRGPRX2 in Host Defense and Inflammation. Journal of dental research 33 32392433
2019 Paeoniflorin inhibits MRGPRX2-mediated pseudo-allergic reaction via calcium signaling pathway. Phytotherapy research : PTR 32 31667930
2018 Rocuronium Hypersensitivity: Does Off-Target Occupation of the MRGPRX2 Receptor Play a Role? The journal of allergy and clinical immunology. In practice 32 30315997
2019 Inhibitory function of Shikonin on MRGPRX2-mediated pseudo-allergic reactions induced by the secretagogue. Phytomedicine : international journal of phytotherapy and phytopharmacology 31 32032836
2023 PACAP activates MRGPRX2 on meningeal mast cells to drive migraine-like pain. Scientific reports 30 37516794
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2021 Resveratrol inhibits MRGPRX2-mediated mast cell activation via Nrf2 pathway. International immunopharmacology 29 33550032
2020 Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2). Molecules (Basel, Switzerland) 29 32106575
2021 Lactic acid suppresses MRGPRX2 mediated mast cell responses. Cellular immunology 25 34399172
2021 MrgprX2 regulates mast cell degranulation through PI3K/AKT and PLCγ signaling in pseudo-allergic reactions. International immunopharmacology 25 34920312
2018 MrgX2‑mediated internalization of LL‑37 and degranulation of human LAD2 mast cells. Molecular medicine reports 25 30280189
2005 Proadrenomedullin N-terminal peptide and cortistatin activation of MrgX2 receptor is based on a common structural motif. European journal of pharmacology 25 16111673
2023 Mas-related G protein-coupled receptor MRGPRX2 in human basophils: Expression and functional studies. Frontiers in immunology 24 36726977
2022 β-arrestin-1 and β-arrestin-2 Restrain MRGPRX2-Triggered Degranulation and ERK1/2 Activation in Human Skin Mast Cells. Frontiers in allergy 24 35910860
2019 Phenothiazine antipsychotics exhibit dual properties in pseudo-allergic reactions: Activating MRGPRX2 and inhibiting the H1 receptor. Molecular immunology 23 31051313
2023 MRGPRX2, drug pseudoallergies, inflammatory diseases, mechanisms and distinguishing MRGPRX2- and IgE/FcεRI-mediated events. British journal of clinical pharmacology 22 37430437
2020 MRGPRX2 activation in mast cells by neuromuscular blocking agents and other agonists: Modulation by sugammadex. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 22 33275825
2022 Opioid toxicity: histamine, hypersensitivity, and MRGPRX2. Archives of toxicology 21 36344690
2021 P17 induces chemotaxis and differentiation of monocytes via MRGPRX2-mediated mast cell-line activation. The Journal of allergy and clinical immunology 20 34111449
2018 Endogenous protein and enzyme fragments induce immunoglobulin E-independent activation of mast cells via a G protein-coupled receptor, MRGPRX2. Scandinavian journal of immunology 20 29484687
2018 Anti-pseudo-allergy effect of isoliquiritigenin is MRGPRX2-dependent. Immunology letters 20 29684393
2017 Mast cell degranulation via MRGPRX2 by isolated human albumin fragments. Biochimica et biophysica acta. General subjects 20 28844982
2022 MrgX2-SNAP-tag/cell membrane chromatography model coupled with liquid chromatography-mass spectrometry for anti-pseudo-allergic compound screening in Arnebiae Radix. Analytical and bioanalytical chemistry 19 35697810
2021 MRGPRX2 mediates immediate-type pseudo-allergic reactions induced by iodine-containing iohexol. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 33524790
2021 Murepavadin, a Small Molecule Host Defense Peptide Mimetic, Activates Mast Cells via MRGPRX2 and MrgprB2. Frontiers in immunology 19 34248979
2022 Luteolin inhibits FcεRΙ- and MRGPRX2-mediated mast cell activation by regulating calcium signaling pathways. Phytotherapy research : PTR 18 35315143
2021 Authentic and Ectopically Expressed MRGPRX2 Elicit Similar Mechanisms to Stimulate Degranulation of Mast Cells. Cells 18 33673037
2022 Patient Characteristics Associated With Reactions to Mrgprx2-Activating Drugs in an Electronic Health Record-Linked Biobank. The journal of allergy and clinical immunology. In practice 17 36356925
2021 Cytokine Stimulation by MRGPRX2 Occurs with Lower Potency than by FcεRI Aggregation but with Similar Dependence on the Extracellular Signal-Regulated Kinase 1/2 Module in Human Skin Mast Cells. The Journal of investigative dermatology 17 34329659
2020 Identification of the dog orthologue of human MAS-related G protein coupled receptor X2 (MRGPRX2) essential for drug-induced pseudo-allergic reactions. Scientific reports 17 32999394
2020 Roxithromycin inhibits compound 48/80-induced pseudo-allergy via the MrgprX2 pathway both in vitro and in vivo. Cellular immunology 17 33129497
2019 Isosalvianolic acid C-induced pseudo-allergic reactions via the mast cell specific receptor MRGPRX2. International immunopharmacology 17 30875538
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2024 Proinflammatory chemokine CXCL14 activates MAS-related G protein-coupled receptor MRGPRX2 and its putative mouse ortholog MRGPRB2. Communications biology 16 38184723
2023 DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis. The Journal of allergy and clinical immunology 16 36804596
2023 Rosmarinic acid ameliorates skin inflammation and pruritus in allergic contact dermatitis by inhibiting mast cell-mediated MRGPRX2/PLCγ1 signaling pathway. International immunopharmacology 16 36931000
2024 MRGPRX2 antagonist GE1111 attenuated DNFB-induced atopic dermatitis in mice by reducing inflammatory cytokines and restoring skin integrity. Frontiers in immunology 15 38817611
2023 Inhibition of Mast Cell Degranulation in Atopic Dermatitis by Celastrol through Suppressing MRGPRX2. Disease markers 15 36712922
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2024 Quercetin Attenuates MRGPRX2-Mediated Mast Cell Degranulation via the MyD88/IKK/NF-κB and PI3K/AKT/ Rac1/Cdc42 Pathway. Journal of inflammation research 13 39398230
2022 The Number of MRGPRX2-Expressing Cells Is Increased in Skin Lesions of Patients With Indolent Systemic Mastocytosis, But Is Not Linked to Symptom Severity. Frontiers in immunology 13 35958589
2021 MYO1F Regulates IgE and MRGPRX2-Dependent Mast Cell Exocytosis. Journal of immunology (Baltimore, Md. : 1950) 13 33941653
2020 Measurement and Functional Analysis of the Mas-Related G Protein-Coupled Receptor MRGPRX2 on Human Mast Cells and Basophils. Methods in molecular biology (Clifton, N.J.) 13 32766979