MRGPRD

Target id: 152

Nomenclature: MRGPRD

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

This receptor has a proposed ligand; see the Latest Pairings page for more information.

   GtoImmuPdb view: OFF :     Currently no data for MRGPRD in GtoImmuPdb

Gene and Protein Information
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
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
Database Links
Specialist databases
GPCRDB mrgrd_human (Hs), mrgrd_mouse (Mm), mrgrd_rat (Rn)
Other databases
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
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
Ligand Sp. Action Affinity Units Reference
β-alanine Rn Agonist 4.8 pEC50 19
pEC50 4.8 (EC50 1.4x10-5 M) [19]
β-alanine Hs Full agonist 4.8 pEC50 19-20
pEC50 4.8 (EC50 1.5x10-5 M) [19-20]
β-alanine Mm Agonist 4.4 pEC50 19
pEC50 4.4 (EC50 4.4x10-5 M) [19]
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].
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
Gq/G11 family
Adenylate cyclase inhibition
Phospholipase C stimulation
References:  4,16
Tissue Distribution
MRGPRD expression is confined to the neurons with persistent Runx1 expression.
Species:  Mouse
Technique:  in situ hybridisation
References:  13
A subset of dorsal root ganglion sensory neurons. Not detected in any other tissue except trigeminal ganglia in neonatal mouse.
Species:  Mouse
Technique:  in situ hybridisation
References:  5
Expressed predominantly in the population of nonpeptidergic, TRPV1-negative, C-polymodal nociceptors.
Species:  Mouse
Technique:  Immunocytochemistry
References:  17
Exclusively expressed in nonpeptidergic neurons that innervate the epidermis
Species:  Mouse
Technique:  Immunohistochemistry
References:  24
Dorsal root ganglion, testis
Species:  Rat
Technique:  RT-PCR
References:  15
Primarily expressed in the dorsal root ganglia. Moderately expressed in the testes, urinary bladder, arteries and uterus.
Species:  Rat
Technique:  RT-PCR
References:  19
Small diameter dorsal root ganglion neurons (C fibers)
Species:  Rat
Technique:  in situ hybridisation
References:  19
Newborn dorsal root ganglia, adult dorsal root ganglia and trigeminal ganglia
Species:  Rat
Technique:  In situ hybridisation
References:  23
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
Activation of MRGPRD inhibits KCNQ/M-type potassium channels and increases phasic neuron excitability.
Species:  Rat
Tissue:  Dorsal root ganglion
References:  4
Physiological Consequences of Altering Gene Expression
C-polymodal nociceptor (CPM) cells in MRGPRD -/- mice exhibit reduced sensitivity to mechanical and thermal stimuli. CPM cells in MRGPRD -/- mice also show decreased excitability in vitro.
Species:  Mouse
Tissue:  Cutaneous sensory neurons
Technique:  Gene knock-in
References:  17
Ablation of MRGPRD nociceptors in cutaneous C-fibers does not affect formalin-induced nocifensive behaviour.
Species:  Mouse
Tissue:  Spinal cord
Technique:  Genetic ablation
References:  18
Ablation of MRGPRD+ neurons do not affect the behavioral responses to multiple prurotogens.
Species:  Mouse
Tissue:  MRGPRD+ neurons
Technique:  Genetic ablation
References:  9
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 Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Mrgprdtm1Mjz|Rettm1Ddg|Tg(Wnt1-cre)11Rth Mrgprdtm1Mjz/?,Rettm1Ddg/Rettm1Ddg,Tg(Wnt1-cre)11Rth/0
involves: 129 * 129S1/Sv * C57BL/6 * C57BL/6J * CBA/J
MGI:2447280  MGI:3033142  MGI:97902  MP:0008415 abnormal neurite morphology PMID: 17553423 
Mrgprdtm1Mjz|Mrgprdtm2.1(DTR)Mjz Mrgprdtm1Mjz/Mrgprdtm2.1(DTR)Mjz
involves: 129S1/Sv
MGI:3033142  MP:0002882 abnormal neuron morphology PMID: 19451647 
Mrgprdtm1Mjz|Mrgprdtm2.1(DTR)Mjz Mrgprdtm1Mjz/Mrgprdtm2.1(DTR)Mjz
involves: 129S1/Sv
MGI:3033142  MP:0002736 abnormal nociception after inflammation PMID: 19451647 
Mrgprdtm1.1(cre)And Mrgprdtm1.1(cre)And/Mrgprdtm1.1(cre)And
B6.129S1-Mrgprd
MGI:3033142  MP:0003463 abnormal single cell response PMID: 19571152 
Mrgprdtm1Mjz Mrgprdtm1Mjz/Mrgprdtm1Mjz
B6.129S1-Mrgprd
MGI:3033142  MP:0003463 abnormal single cell response PMID: 19571152 
Mrgprdtm1Mjz|Mrgprdtm2.1(DTR)Mjz Mrgprdtm1Mjz/Mrgprdtm2.1(DTR)Mjz
involves: 129S1/Sv
MGI:3033142  MP:0005498 hyporesponsive to tactile stimuli PMID: 19451647 
Mrgprdtm1.1(cre)And Mrgprdtm1.1(cre)And/Mrgprdtm1.1(cre)And
B6.129S1-Mrgprd
MGI:3033142  MP:0005498 hyporesponsive to tactile stimuli PMID: 19571152 
Mrgprdtm1Mjz Mrgprdtm1Mjz/Mrgprdtm1Mjz
B6.129S1-Mrgprd
MGI:3033142  MP:0005498 hyporesponsive to tactile stimuli PMID: 19571152 
Mrgprdtm1.1(cre)And Mrgprdtm1.1(cre)And/Mrgprdtm1.1(cre)And
B6.129S1-Mrgprd
MGI:3033142  MP:0001973 increased thermal nociceptive threshold PMID: 19571152 
Mrgprdtm1Mjz Mrgprdtm1Mjz/Mrgprdtm1Mjz
B6.129S1-Mrgprd
MGI:3033142  MP:0001973 increased thermal nociceptive threshold PMID: 19571152 
Mrgprdtm4.1(COP4)Mjz Mrgprdtm4.1(COP4)Mjz/Mrgprdtm4.1(COP4)Mjz
involves: 129P2/OlaHsd * C57BL/6
MGI:3033142  MP:0002169 no abnormal phenotype detected PMID: 19846708 
General Comments
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

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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. U.S.A.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. U.S.A.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. Neuron49 (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. Cell106 (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. U.S.A.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. U.S.A.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. Cell139 (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. Neuron54 (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. Pain151 (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, Watanabe T, Moriya T, Itoh Y, Hinuma S. (2004) Identification of a G protein-coupled receptor specifically responsive to beta-alanine. J Biol Chem279: 23559-23564. [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 Screen18 (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. U.S.A.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. Neuron45 (1): 17-25. [PMID:15629699]

Contributors

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How to cite this page

Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: MRGPRD. Last modified on 30/07/2015. Accessed on 13/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=152.