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MRGPRX2

Family: Class A Orphans

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Transduction Mechanisms
Tissue Distribution
Physiological Functions
Physiological Consequences of Altering Gene Expression
Biologically Significant Variants
General Comments
References
Gene and Protein Information
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, member X2
Previous and Unofficial Names
MRGX2
Mrgprb10
MAS-related GPR, member X2
MrgX2
Database Links
ChEMBL Target 101353 (Hs)
Ensembl ENSG00000183695 (Hs)
Entrez Gene 117194 (Hs)
GeneCards MRGPRX2 (Hs)
HomoloGene 24986 (Hs)
Human Protein Reference Database 06247 (Hs)
InterPro Q96LB1 (Hs)
KEGG Gene hsa:117194 (Hs)
OMIM 607228 (Hs)
PharmGKB Gene PA142671335 (Hs)
Protein Ontology (PRO) PRO:000001703 (Hs)
RefSeq Nucleotide NM_054030 (Hs)
RefSeq Protein NP_054030 (Hs)
TreeFam ENSG00000183695 (Hs)
UniGene Hs. 350566 (Hs)
UniProt Q96LB1 (Hs)
Wikipedia MRGPRX2
Orphan and other 7TM receptors
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
PAMP-12 (human) Hs Full agonist 7.24 – 7.68 pEC50 6
CST-14 {Sp: Mouse, Rat} Hs Full agonist 7.31 – 7.6 pEC50 6,12
compound 2 [PMID:19230660] Hs Full agonist 6.5 pEC50 10
Agonist Comments
A set of ligands have been identified to be agonists of MRGPRX2, with cortistatin 14 to be the highest potency agonist [12] . Cortistatin and PAMP are proposed to be MRGPRX2 receptor surrogates, as both ligands have not been shown to activate MRGPRX2 in vivo [11]. MRGPRX2 responded to angiotensin metabolite stimulation [4]. PMX-53 is found to be a low-affinity agonist for MRGX2 [14]. Compound 48/80, peptides E7, E7S and PMX-53 activate MRGPRX2 in mast cells [7]. MRGPRX2 is reported to be a receptor for the antimicrobial peptide LL-37 in human mast cells [13].
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
Gq/G11 family 		Adenylate cyclase inhibition
Phospholipase C stimulation
References:  6,12,15
Tissue Distribution
Lumbar dorsal root ganglion, cervical dorsal root ganglion, thoracic dorsal root ganglion, testis, small intestibe, spinal cord, pancreas, lung, heart, thymus, colon
Species:  Human
Technique:  RT-PCR
References:  12
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:  12
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:  1
Small sensory neurons in dorsal root ganglia, adrenal chromaffin cells
Species:  Human
Technique:  Immunohistochemistry
References:  6
Thymocytes
Species:  Human
Technique:  Microarray analysis and RT-PCR
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:  14
Human cord mast cells. Also highly expressed in skin, adipose tissue, bladder and colon. Lower levels of transcripts were detected in testis, uterus, stomach, eosophagus, small intestine, duodenum, lymph node, spleen, trachea, prostate and dorsal root ganglia.
Species:  Human
Technique:  RT-PCR
References:  15
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:  1
T lymphocytes
Species:  Human
Technique:  Microarray analysis
References:  16
Small sensory neurons of dorsal root ganglia, testis, skin, adipose, bladder, skeletal muscle, small intestine, aorta, uterus
Species:  Human
Technique:  RT-PCR
References:  6
Physiological Functions
Involved in LL-37-induced chemotaxis, degranulation and chemokine productions in mast cells.
Species:  Human
Tissue:  Mast cell
References:  13
Involved in compound 48/80-induced mast cell degranulation
Species:  Human
Tissue:  Mast cell
References:  7
Physiological Consequences of Altering Gene Expression
Silencing MrgprX2 expresion inhibits LL-37 and cortistatin-induced mast cell degranulation.
Species:  Human
Tissue:  Mast cell
Technique:  RNA interference
References:  13
Biologically Significant Variants
N62S
SNP accession:  rs10833049 
Type:  Naturally occurring SNPs.
Species:  Human
References: 
N16H
SNP accession:  rs11024970 
Type:  Naturally occurring SNPs.
Species:  Human
References: 
V43I
SNP accession:  rs11823569 
Type:  Naturally occurring SNPs.
Species:  Human
References: 
General Comments
It was shown that unlike most GPCRs, MRGPRX2 was resistant to LL-37-induced phosphorylation, desensitization and internalization [13].

Of the eight human Mas-related GPCRs (MRGs), four (MRGPRD, MRGPRE, MRGPRF and MRGPRG) have clear orthologues in rodents, whereas the cluster of genes including human MRGPRX1, MRGPRX2, MRGPRX3 and MRGPRX4 is found only in primates and is replaced in rodents with a family of genes (>25 in mice, ~10 in rats) which have no obvious human counterparts [3]. Certain rodent MRGs have been reported to respond to adenine [2] and to RF-amide peptides including neuropeptide FF [5,8] but the relevance of these findings to man is unclear. MRGs are expressed predominantly in small diameter sensory neurons of the dorsal root ganglia, where there is emerging evidence that they may be mediators of histamine-independent itch [9,17].

REFERENCES

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1. 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]

2. Bender, E; Buist, A; Jurzak, M; Langlois, X; Baggerman, G; Verhasselt, P; Ercken, M; Guo, HQ; Wintmolders, C; Van den Wyngaert, I; et al.. (2002) Characterization of an orphan G protein-coupled receptor localized in the dorsal root ganglia reveals adenine as a signaling molecule. Proc. Natl. Acad. Sci. U.S.A., 99 (13): 8573-8. [PMID:12084918]

3. 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]

4. 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]

5. Han, SK; Dong, X; Hwang, JI; Zylka, MJ; Anderson, DJ; Simon, MI. (2002) Orphan G protein-coupled receptors MrgA1 and MrgC11 are distinctively activated by RF-amide-related peptides through the Galpha q/11 pathway. Proc. Natl. Acad. Sci. U.S.A., 99 (23): 14740-5. [PMID:12397184]

6. 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]

7. 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]

8. Lee, MG; Dong, X; Liu, Q; Patel, KN; Choi, OH; Vonakis, B; Undem, BJ. (2008) Agonists of the MAS-related gene (Mrgs) orphan receptors as novel mediators of mast cell-sensory nerve interactions. J. Immunol., 180 (4): 2251-5. [PMID:18250432]

9. Liu, Q; Tang, Z; Surdenikova, L; Kim, S; Patel, KN; Kim, A; Ru, F; Guan, Y; Weng, HJ; Geng, Y; Undem, BJ; Kollarik, M; Chen, ZF; Anderson, DJ; Dong, X. (2009) Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell, 139 (7): 1353-65. [PMID:20004959]

10. 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]

11. 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]

12. Robas, N., Mead, E. and Fidock, M. (2003) MrgX2 is a high potency cortistatin receptor expressed in dorsal root ganglion. J Biol Chem, 278: 44400-44404. [PMID:12915402]

13. 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]

14. 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]

15. 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]

16. 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]

17. Wilson, SR; Gerhold, KA; Bifolck-Fisher, A; Liu, Q; Patel, KN; Dong, X; Bautista, DM. (2011) TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat. Neurosci., 14 (5): 595-602. [PMID:21460831]

To cite this database page, please use the following:

Wen Chiy Liew.
Class A Orphans: MRGPRX2. Last modified on 14/12/2012. Accessed on 26/05/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=157.


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