MRGPRD
Target id: 152
Nomenclature: MRGPRD
Family: Class A Orphans
This receptor has a proposed ligand; see the Latest Pairings page for more information.
Contents:
- Gene and Protein Information
- Previous and Unofficial Names
- Database Links
- Natural/Endogenous Ligands
- Agonists
- Transduction Mechanisms
- Tissue Distribution
- Functional Assays
- Physiological Functions
- Physiological Consequences of Altering Gene Expression
- Phenotypes, Alleles and Disease Models
- General Comments
- References
- Contributors
- How to cite this page
Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 321 | 11q13.3 | MRGPRD | MAS related GPR family member D | |
| Mouse | 7 | 321 | 7 F5 | Mrgprd | MAS-related GPR, member D | |
| Rat | 7 | 319 | 1q42 | Mrgprd | MAS related GPR family member D | |
| Previous and Unofficial Names |
| TGR7 | Beta-alanine receptor | G-protein coupled receptor TGR7 | mas-related G-protein coupled receptor member D | MAS-related gene D | MAS-related GPR |
| Database Links |
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| Specialist databases | |
| GPCRdb | mrgrd_human (Hs), mrgrd_mouse (Mm), mrgrd_rat (Rn) |
| Other databases | |
| Alphafold | Q8TDS7 (Hs), Q91ZB8 (Mm), Q7TN41 (Rn) |
| ChEMBL Target | CHEMBL4523899 (Hs) |
| Ensembl Gene | ENSG00000172938 (Hs), ENSMUSG00000051207 (Mm), ENSRNOG00000013448 (Rn) |
| Entrez Gene | 116512 (Hs), 211578 (Mm), 293648 (Rn) |
| Human Protein Atlas | ENSG00000172938 (Hs) |
| KEGG Gene | hsa:116512 (Hs), mmu:211578 (Mm), rno:293648 (Rn) |
| OMIM | 607231 (Hs) |
| Pharos | Q8TDS7 (Hs) |
| RefSeq Nucleotide | NM_198923 (Hs), NM_203490 (Mm), NM_001001506 (Rn) |
| RefSeq Protein | NP_944605 (Hs), NP_987075 (Mm), NP_001001506 (Rn) |
| UniProtKB | Q8TDS7 (Hs), Q91ZB8 (Mm), Q7TN41 (Rn) |
| Wikipedia | MRGPRD (Hs) |
| Natural/Endogenous Ligands |
| β-alanine |
| Comments: Proposed ligand, two publications |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific agonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| It was reported that β-alanine caused internalisation of rat MRGPRD receptor into punctate intracellular vesicles [15]. However, the level of internalisation of MRGPRD was reduced when MRGPRD was coexpressed with MRGPRE [15]. β-alanine potency was slightly elevated in cells coexpressing rat MRGPRD and MRFPRE [15]. MRGPRD showed significant arachidonic acid release in response to Ang-(1-7) stimulation [7]. MRGPRD showed high sensitivity to extracellar ATP but little or no sensitivity to other putative nociceptive agonists, such as capsaicin, cinnamaldehyde, menthol, pH 6.0, and glutamate [6]. An endogenous peptide with a high degree of sequence similarity to ang-(1-7), alamandine, was shown to promote NO release in MrgD-transfected cells. The binding of alamandine to MRGPRD to was shown to be blocked by D-Pro7-angiotensin-(1–7), β-alanine and PD123319 [10]. |
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| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
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Gi/Go family Gq/G11 family |
Adenylyl cyclase inhibition Phospholipase C stimulation |
| References: 4,16 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| MRGPRD+ fibers have been shown to specifically innervate in the stratum granulosom of the epidermis [24] and terminate in inner lamina II of the spinal cord dorsal horn [18]. MRGPRD is expressed in unmyelinated sensory afferents that bind isolectin-B4 (IB4) and express the ectonucleotidase prostatic acid phosphotase and the ATP-gated ion channel P2X3 [5,17,23-24]. It is found that MRGPRD+ neurons were monosynaptically connected to most known classes of substantia gelatinosa neurons, including radial, tonic central, transcient central, vertical and antenna cells, but not islet cell class [21]. | ||||||||
| Functional Assay Comments |
| It is demonstrated that MRGPRD and MRGPRE can be coexpressed and form heterodimers [15]. |
| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| Cavanaugh et al. show that genetic ablation in MRGPRD+ neuron of adult mice decreased behavioral sensitivity to mechanical stimuli but not to thermal stimuli [2]. | ||||||||||
| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| General Comments |
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The expression of MRGPRD was shown to be regulated by Runx1 and nerve growth factor [3,14]. MRGPRD+ neurons display nociceptor-like properties: long-duration action potentials, tetradotoxin-resistant Na+ current, and Ca2+ currents that are inhibited by mu opioids [6]. 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 [5]. Certain rodent MRGs have been reported to respond to adenine [1] and to RF-amide peptides including neuropeptide FF [8,11] 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 [12,22]. |
References
1. 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 USA, 99 (13): 8573-8. [PMID:12084918]
2. Cavanaugh DJ, Lee H, Lo L, Shields SD, Zylka MJ, Basbaum AI, Anderson DJ. (2009) Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci USA, 106 (22): 9075-80. [PMID:19451647]
3. Chen CL, Broom DC, Liu Y, de Nooij JC, Li Z, Cen C, Samad OA, Jessell TM, Woolf CJ, Ma Q. (2006) Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain. Neuron, 49 (3): 365-77. [PMID:16446141]
4. Crozier RA, Ajit SK, Kaftan EJ, Pausch MH. (2007) MrgD activation inhibits KCNQ/M-currents and contributes to enhanced neuronal excitability. J Neurosci, 27 (16): 4492-6. [PMID:17442834]
5. 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]
6. Dussor G, Zylka MJ, Anderson DJ, McCleskey EW. (2008) Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors. J Neurophysiol, 99 (4): 1581-9. [PMID:18234974]
7. 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]
8. 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 USA, 99 (23): 14740-5. [PMID:12397184]
9. Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI, Basbaum AI, Han SK. (2009) TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci USA, 106 (27): 11330-5. [PMID:19564617]
10. Lautner RQ, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T, Costa-Fraga F, Jankowski J, Jankowski V, Sousa F, Alzamora A et al.. (2013) Discovery and characterization of alamandine: a novel component of the Renin-Angiotensin system. Circ Res, 112 (8): 1104-11. [PMID:23446738]
11. 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]
12. 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]
13. Liu Y, Yang FC, Okuda T, Dong X, Zylka MJ, Chen CL, Anderson DJ, Kuner R, Ma Q. (2008) Mechanisms of compartmentalized expression of Mrg class G-protein-coupled sensory receptors. J Neurosci, 28 (1): 125-32. [PMID:18171930]
14. Luo W, Wickramasinghe SR, Savitt JM, Griffin JW, Dawson TM, Ginty DD. (2007) A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons. Neuron, 54 (5): 739-54. [PMID:17553423]
15. Milasta S, Pediani J, Appelbe S, Trim S, Wyatt M, Cox P, Fidock M, Milligan G. (2006) Interactions between the Mas-related receptors MrgD and MrgE alter signalling and trafficking of MrgD. Mol Pharmacol, 69 (2): 479-91. [PMID:16282220]
16. Qi X, Tang J, Pramanik R, Schultz RM, Shirasawa S, Sasazuki T, Han J, Chen G. (2004) p38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor. J Biol Chem, 279 (21): 22138-44. [PMID:15037631]
17. Rau KK, McIlwrath SL, Wang H, Lawson JJ, Jankowski MP, Zylka MJ, Anderson DJ, Koerber HR. (2009) Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors. J Neurosci, 29 (26): 8612-9. [PMID:19571152]
18. Shields SD, Cavanaugh DJ, Lee H, Anderson DJ, Basbaum AI. (2010) Pain behavior in the formalin test persists after ablation of the great majority of C-fiber nociceptors. Pain, 151 (2): 422-9. [PMID:20832171]
19. Shinohara T, Harada M, Ogi K, Maruyama M, Fujii R, Tanaka H, Fukusumi S, Komatsu H, Hosoya M, Noguchi Y et al.. (2004) Identification of a G protein-coupled receptor specifically responsive to beta-alanine. J Biol Chem, 279 (22): 23559-64. [PMID:15037633]
20. 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]
21. Wang H, Zylka MJ. (2009) Mrgprd-expressing polymodal nociceptive neurons innervate most known classes of substantia gelatinosa neurons. J Neurosci, 29 (42): 13202-9. [PMID:19846708]
22. 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]
23. Zylka MJ, Dong X, Southwell AL, Anderson DJ. (2003) Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family. Proc Natl Acad Sci USA, 100 (17): 10043-8. [PMID:12909716]
24. Zylka MJ, Rice FL, Anderson DJ. (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron, 45 (1): 17-25. [PMID:15629699]
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