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MRGPRX2

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 157

Nomenclature: MRGPRX2

Family: Class A Orphans

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 330 11p15.1 MRGPRX2 MAS related GPR family member X2
Previous and Unofficial Names Click here for help
Mrgprb10 | MRGX2
Database Links Click here for help
Specialist databases
GPCRdb mrgx2_human (Hs)
Other databases
Alphafold Q96LB1 (Hs)
ChEMBL Target CHEMBL5849 (Hs)
Ensembl Gene ENSG00000183695 (Hs)
Entrez Gene 117194 (Hs)
Human Protein Atlas ENSG00000183695 (Hs)
KEGG Gene hsa:117194 (Hs)
OMIM 607228 (Hs)
Pharos Q96LB1 (Hs)
RefSeq Nucleotide NM_054030 (Hs)
RefSeq Protein NP_054030 (Hs)
UniProtKB Q96LB1 (Hs)
Wikipedia MRGPRX2 (Hs)
Natural/Endogenous Ligands Click here for help
PAMP-20 {Sp: Human}
Comments: Proposed ligand, two publications

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PAMP-12 (human) Peptide Hs Full agonist 7.2 – 7.7 pEC50 10
⤷ pEC50 7.2 – 7.7 (EC50 5.72x10-8 – 2.08x10-8 M) [10]
cortistatin-14 {Sp: Mouse, Rat} Peptide Click here for species-specific activity table Hs Full agonist 6.9 – 7.6 pEC50 10,12,16-17
⤷ pEC50 6.9 – 7.6 (EC50 4.85x10-8 – 2.5x10-8 M) [10,12,16-17]
compound 2 [PMID: 19230660] Small molecule or natural product Hs Full agonist 6.5 pEC50 13
⤷ pEC50 6.5 [13]
(R)-ZINC-3573 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 6.1 pEC50 12
⤷ pEC50 6.1 (EC50 7.6x10-7 M) [12]
substance P {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Hs Agonist 6.0 pEC50 12,14
⤷ pEC50 6.0 (EC50 1.071x10-6 M) [12,14]
Description: In a calcium mobilisation asay.
compound 48/80 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 5.7 pEC50 12
⤷ pEC50 5.7 (EC50 1.8x10-6 M) [12]
TAN-67 Small molecule or natural product Hs Agonist 5.7 pEC50 7,12,17
⤷ pEC50 5.7 (EC50 1.82x10-6 M) [7,12,17]
Description: Assayed using racemic TAN-67, the more active stereoisomer is the (4aS,12aR).
GPR15L {Sp: Human} Peptide Click here for species-specific activity table Immunopharmacology Ligand Hs Agonist 5.7 pEC50 22
⤷ pEC50 5.7 (EC50 1.9x10-6 M) [22]
Description: Determined in a FLIPR calcium imaging assay using HEK cells heterologously expressing hMRGPRX2
SRIF-28 {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Hs Agonist 5.4 pEC50 17
⤷ pEC50 5.4 (EC50 4.17x10-6 M) [17]
Description: In a calcium mobilisation assay.
ERAS-5024 Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.4 pEC50 5
⤷ pEC50 5.4 (EC50 4.2x10-6 M) [5]
Agonist Comments
A diverse range of substances has been reported to be agonists of MRGPRX2, with cortistatin 14 the highest potency agonist in assays of calcium mobilisation [16] also confirmed in an independent study using an arrestin recruitment assay [17]. Compound 48/80 is used experimentally as the prototype MRGPRX2 agonist [12]. Cortistatin and PAMP are proposed to be MRGPRX2 receptor surrogates, as both ligands have not been shown to activate MRGPRX2 in vivo [15]. MRGPRX2 responded to angiotensin metabolite stimulation [9]. PMX-53 is found to be a low-affinity agonist for MRGX2 [20]. Other agonists such as peptides E7, E7S and PMX-53 activate MRGPRX2 in mast cells [11]. MRGPRX2 is reported to be a receptor for the antimicrobial peptide LL-37 in human mast cells [19].
Antagonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
QWF Peptide Immunopharmacology Ligand Hs Antagonist - - 4
⤷ [4]
Antagonist Comments
The MRGPRX2 antagonist/inverse agonist EP262 (structure not disclosed July 2024) is a clinical candidate treament for mast cell-driven diseases, such as chronic spontaneous urticaria and cold urticaria.
Immunopharmacology Comments
Expression of MRGPRX2 was initially reported predominantly in sensory neurons of the dorsal root ganglion. More recently expression has been detected in human mast cells. In these cells the receptor is activated by the antimicrobial peptide LL-37, resulting in calcium mobilisation and degranulation [14,19]. Of additional interest is the presence of elevated MRGPRX2 expression in skin mast cells derived from chronic urticaria sufferers, accompanied by eosinophil infiltration [8]. Eosinophil-derived MBP (eosinophil major basic protein) and EPO (eosinophil peroxidase) have also been shown to stimulate mast cells via MRGPRX2 [8], providing a mast cell-eosinophil cross-talk leading to disease exacerbation. Data reported in [3] further implicate MRGPRX2 inflammatory conditions associated with itch and erythema. It is reasoned that pharmacological antagonism of MRGPRX2 activity could represent a novel mechanism for treating IgE-independent inflammatory reactions, including anaphylaxis. Thus, MRGPRX2 is considered a molecular target for pharmacological intervention in mast cell-mediated allergic and inflammatory diseases [1].
Cell Type Associations
Immuno Cell Type:  Mast cells
Cell Ontology Term:   mast cell (CL:0000097)
References:  19
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Cellular signalling
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
Gq/G11 family 		Adenylyl cyclase inhibition
Phospholipase C stimulation
References:  10,16,21
Tissue Distribution Click here for help
Dorsal root ganglion (stained strongly in small sensory neurons and moderately in large sensory neurons), CA2, CA3 and CA4 regions in hippocampus, subsets of neurons in the substantia nigra, hypothalamus and medulla, endothelium and vascular smooth muscle of small intestine, spermatocytic precursors in testis. Not detected in cerebral cortex.
Species:  Human
Technique:  Immunohistochemistry
References:  16
Human mast cell line LAD2 and CD34+-derived mast cells. Not detected in immature human mast cell line HMC-1.
Species:  Human
Technique:  RT-PCR
References:  20
Lumbar dorsal root ganglion, cervical dorsal root ganglion, thoracic dorsal root ganglion, testis, small intestine, spinal cord, pancreas, lung, heart, thymus, colon
Species:  Human
Technique:  RT-PCR
References:  16
Hypothalamus, thyroid, pancreas, pituitary gland, lung, stomach, ileum, colon, ovary, testis. Not detected in cerebral cortex, parathyroid and adrenal gland
Species:  Human
Technique:  RT-PCR
References:  2
Small sensory neurons in dorsal root ganglia, adrenal chromaffin cells
Species:  Human
Technique:  Immunohistochemistry
References:  10
Thymocytes
Species:  Human
Technique:  Microarray analysis and RT-PCR
References:  23
Blood vessels and scattered lymphocytes in all tissues investigated (which include cerebral cortex, hypothalamus, pituitary gland, thyroid, parathyroid, adrenal gland, lung, stomach, ileum, colon, pancreas, ovary and testis), gastrointestinal ganglion cells, scattered neurons of neurohypophysis, testicular tubules
Species:  Human
Technique:  Immunohistochemistry
References:  2
T lymphocytes
Species:  Human
Technique:  Microarray analysis
References:  23
Human cord mast cells. Also highly expressed in skin, adipose tissue, bladder and colon. Lower levels of transcripts were detected in testis, uterus, stomach, oesophagus, small intestine, duodenum, lymph node, spleen, trachea, prostate and dorsal root ganglia.
Species:  Human
Technique:  RT-PCR
References:  21
Small sensory neurons of dorsal root ganglia, testis, skin, adipose, bladder, skeletal muscle, small intestine, aorta, uterus
Species:  Human
Technique:  RT-PCR
References:  10
Physiological Functions Click here for help
Involved in LL-37-induced chemotaxis, degranulation and chemokine productions in mast cells.
Species:  Human
Tissue:  Mast cell
References:  19
Involved in compound 48/80-induced mast cell degranulation
Species:  Human
Tissue:  Mast cell
References:  11
Physiological Consequences of Altering Gene Expression Click here for help
Silencing MrgprX2 expresion inhibits LL-37 and cortistatin-induced mast cell degranulation.
Species:  Human
Tissue:  Mast cell
Technique:  RNA interference
References:  19
Biologically Significant Variants Click here for help
Type:  Naturally occurring SNP
Species:  Human
Amino acid change:  V43I
SNP accession:  rs11823569
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  N62S|N62T
Global MAF (%):  32
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 52|25|25|25
Minor allele count:  C=0.316/690
SNP accession:  rs10833049
Validation:  1000 Genomes, HapMap, Frequency
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  N16H
Global MAF (%):  10
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 19|4|12|6
Minor allele count:  G=0.100/219
SNP accession:  rs11024970
Validation:  1000 Genomes, HapMap, Frequency
General Comments
MRGPRX2 is activated by a diverse group of ligands that includes neuropeptides, cysteine proteases, antimicrobial peptides and cationic proteins released from activated eosinophils. Unlike most GPCRs, MRGPRX2 is resistant to LL-37-induced phosphorylation, desensitization and internalization [19].

Of the eight human Mas-related GPCRs (MRGs), four (MRGPRD, MRGPRE, MRGPRF and MRGPRG) have clear orthologues in rodents. The cluster of genes including human MRGPRX1, MRGPRX2, MRGPRX3 and MRGPRX4 is replaced in rodents with a family of MRG genes (>25 in mice, ~10 in rats) that have low homology to human MRGPRX genes [6]. However, one of these mouse MRG genes (encoded by MrgprB2) has been proposed to be orthologous to human MRGPRX2, in that it shares tissue-distribution and as activated by most of the same agonists, and furthermore is encoded in a syntenic chromosomal locus [14]. The low sequence similarity between MRGPRX2 and MrgprB2 is therefore surprising, but is attributed to frequent retrotransposon insertion into the locus in rodent [6]. An MRGPRX2 orthologue has also been described in rat [18].

References

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1. Ali H. (2016) Mas-related G protein coupled receptor-X2: A potential new target for modulating mast cell-mediated allergic and inflammatory diseases. J Immunobiol, 1 (4). [PMID:28090599]

2. Allia E, Tarabra E, Volante M, Cerrato M, Ghigo E, Muccioli G, Papotti M. (2005) Expression of cortistatin and MrgX2, a specific cortistatin receptor, in human neuroendocrine tissues and related tumours. J Pathol, 207 (3): 336-45. [PMID:16161007]

3. Azimi E, Reddy VB, Lerner EA. (2017) Brief communication: MRGPRX2, atopic dermatitis and red man syndrome. Itch (Phila), 2 (1). [PMID:28367504]

4. Azimi E, Reddy VB, Shade KC, Anthony RM, Talbot S, Pereira PJ, Lerner EA. (2016) Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight, 1 (16): e89362. [PMID:27734033]

5. Brooun A, Zhang J, Li C, Lam R, Cheng H, Shoemaker R, Daly J, Olaharski A. (2023) The pharmacologic and toxicologic characterization of the potent and selective KRAS G12D inhibitors ERAS-4693 and ERAS-5024. Toxicol Appl Pharmacol, 474: 116601. [PMID:37321326]

6. Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ. (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell, 106 (5): 619-32. [PMID:11551509]

7. Fujii H, Kawai K, Kawamura K, Mizusuna A, Onoda Y, Murachi M, Tanaka T, Endoh T, Nagase H. (2001) Synthesis of optically active TAN-67, a highly selective delta opioid receptor agonist, and investigation of its pharmacological properties. Drug Des Discov, 17 (4): 325-30. [PMID:11765135]

8. Fujisawa D, Kashiwakura J, Kita H, Kikukawa Y, Fujitani Y, Sasaki-Sakamoto T, Kuroda K, Nunomura S, Hayama K, Terui T et al.. (2014) Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. J Allergy Clin Immunol, 134 (3): 622-633.e9. [PMID:24954276]

9. Gembardt F, Grajewski S, Vahl M, Schultheiss HP, Walther T. (2008) Angiotensin metabolites can stimulate receptors of the Mas-related genes family. Mol Cell Biochem, 319 (1-2): 115-23. [PMID:18636314]

10. Kamohara M, Matsuo A, Takasaki J, Kohda M, Matsumoto M, Matsumoto S, Soga T, Hiyama H, Kobori M, Katou M. (2005) Identification of MrgX2 as a human G-protein-coupled receptor for proadrenomedullin N-terminal peptides. Biochem Biophys Res Commun, 330 (4): 1146-52. [PMID:15823563]

11. Kashem SW, Subramanian H, Collington SJ, Magotti P, Lambris JD, Ali H. (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. Eur J Pharmacol, 668 (1-2): 299-304. [PMID:21741965]

12. Lansu K, Karpiak J, Liu J, Huang XP, McCorvy JD, Kroeze WK, Che T, Nagase H, Carroll FI, Jin J et al.. (2017) In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol, 13 (5): 529-536. [PMID:28288109]

13. Malik L, Kelly NM, Ma JN, Currier EA, Burstein ES, Olsson R. (2009) Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis. Bioorg Med Chem Lett, 19 (6): 1729-32. [PMID:19230660]

14. McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, Dong X. (2015) Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature, 519 (7542): 237-41. [PMID:25517090]

15. Nothacker HP, Wang Z, Zeng H, Mahata SK, O'Connor DT, Civelli O. (2005) Proadrenomedullin N-terminal peptide and cortistatin activation of MrgX2 receptor is based on a common structural motif. Eur J Pharmacol, 519 (1-2): 191-3. [PMID:16111673]

16. Robas N, Mead E, Fidock M. (2003) MrgX2 is a high potency cortistatin receptor expressed in dorsal root ganglion. J Biol Chem, 278 (45): 44400-4. [PMID:12915402]

17. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS et al.. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. J Biomol Screen, 18 (5): 599-609. [PMID:23396314]

18. Subramanian H, Gupta K, Ali H. (2016) Roles of Mas-related G protein-coupled receptor X2 on mast cell-mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases. J Allergy Clin Immunol, 138 (3): 700-10. [PMID:27448446]

19. Subramanian H, Gupta K, Guo Q, Price R, Ali H. (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. J Biol Chem, 286 (52): 44739-49. [PMID:22069323]

20. Subramanian H, Kashem SW, Collington SJ, Qu H, Lambris JD, Ali H. (2011) PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Mol Pharmacol, 79 (6): 1005-13. [PMID:21441599]

21. Tatemoto K, Nozaki Y, Tsuda R, Konno S, Tomura K, Furuno M, Ogasawara H, Edamura K, Takagi H, Iwamura H et al.. (2006) Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors. Biochem Biophys Res Commun, 349 (4): 1322-8. [PMID:16979137]

22. Tseng PY, Hoon MA. (2022) GPR15L is an epithelial inflammation-derived pruritogen. Sci Adv, 8 (24): eabm7342. DOI: 10.1126/sciadv.abm7342 [PMID:35704588]

23. van Hagen PM, Dalm VA, Staal F, Hofland LJ. (2008) The role of cortistatin in the human immune system. Mol Cell Endocrinol, 286 (1-2): 141-7. [PMID:18450367]

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