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MRGPRD

Family: Class A Orphans

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Transduction Mechanisms
Tissue Distribution
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 321 11q13.3 MRGPRD MAS-related GPR, member D
Mouse 7 321 7 F5 Mrgprd MAS-related GPR, member D
Rat 7 319 1q42 Mrgprd MAS-related GPR, member D
Previous and Unofficial Names
TGR7
MRGD
mrgD
MAS-related GPR, member D
MRGPRD
Beta-alanine receptor
G-protein coupled receptor TGR7
mas-related G protein-coupled MRGD
mas-related G-protein coupled receptor member D
MrgD
MAS-related G-protein coupled receptor, member D
MAS-related gene D
MRGD G protein-coupled receptor
LOC211578
Gm499
Database Links
Ensembl ENSG00000172938 (Hs), ENSMUSG00000051207 (Mm), ENSRNOG00000013448 (Rn)
Entrez Gene 116512 (Hs), 211578 (Mm), 293648 (Rn)
GeneCards MRGPRD (Hs)
GenitoUrinary Development Molecular Anatomy Project Mrgprd (Mm)
HomoloGene 18893 (Hs)
Human Protein Reference Database 06250 (Hs)
InterPro Q8TDS7 (Hs), Q91ZB8 (Mm), Q7TN41 (Rn)
KEGG Gene hsa:116512 (Hs), mmu:211578 (Mm), rno:293648 (Rn)
OMIM 607231 (Hs)
PharmGKB Gene PA134978563 (Hs)
PhosphoSitePlus Q8TDS7 (Hs), Q91ZB8 (Mm), Q7TN41 (Rn)
Protein Ontology (PRO) PRO:000001602 (Hs)
RefSeq Nucleotide NM_198923 (Hs), NM_203490 (Mm), NM_001001506 (Rn)
RefSeq Protein NP_944605 (Hs), NP_987075 (Mm), NP_001001506 (Rn)
TreeFam ENSG00000172938 (Hs), ENSMUSG00000051207 (Mm), ENSRNOG00000013448 (Rn)
UniGene Hs. 527802 (Hs)
UniProt Q8TDS7 (Hs), Q91ZB8 (Mm), Q7TN41 (Rn)
Wikipedia MRGPRD
Orphan and other 7TM receptors
Natural/Endogenous Ligand(s)
β-alanine
Comments: Proposed ligand, single publication
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
β-alanine Hs Full agonist 4.82 pEC50 18
Agonist Comments
It is reported that β-alanine caused internalisation of rat MRGPRD receptor into punctate intracellular vesicles [14]. However, the level of internalisation of MRGPRD is reduced when MRGPRD is coexpressed with MRGPRE [14]. β-alanine potency was slightly elevated in cells coexpressing rat MRGPRD and MRFPRE [14]. 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 sensivity to other putative nociceptive agonists, such as capsaicin, cinnamaldehyde, menthol, pH 6.0, and glutamate [6].
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
Gq/G11 family 		Adenylate cyclase inhibition
Phospholipase C stimulation
References:  4,15
Tissue Distribution
MRGPRD expression is confined to the neurons with persistant Runx1 expression.
Species:  Mouse
Technique:  in situ hybridisation
References:  12
Expressed predominantly in the population of nonpeptidergic, TRPV1-negative, C-polymodal nociceptors.
Species:  Mouse
Technique:  Immunocytochemistry
References:  16
Exclusively expressed in nonpeptidergic neurons that innervate the epidermis within skin.
Species:  Mouse
Technique:  immunohistochemistry
References:  22
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
Dorsal root ganglion, testis
Species:  Rat
Technique:  RT-PCR
References:  14
Newborn dorsal root ganglia, adult dorsal root ganglia and trigeminal ganglia
Species:  Rat
Technique:  In situ hybridisation
References:  21
Small diameter dorsal root ganglion neurons (C fibers)
Species:  Rat
Technique:  in situ hybridisation
References:  18
Primarily expressed in the dorsal root ganglia. Moderately expressed in the testes, urinary bladder, arteries and uterus.
Species:  Rat
Technique:  RT-PCR
References:  18
Tissue Distribution Comments
MRGPRD+ fibers have been shown to specifically innervate in the stratum granulosom of the epidermis [22] and terminate in inner lamina II of the spinal cord dorsal horn [17]. 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 [5,16,21-22]. 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 [19].
Functional Assay Comments
It is demonstrated that MRGPRD and MRGPRE can be coexpressed and form heterodimers [14].
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
Ablation of MRGPRD+ neurons do not affect the behavioral responses to multiple prurotogens.
Species:  Mouse
Tissue:  MRGPRD+ neurons
Technique:  Genetic ablation
References:  9
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:  16
Ablation of MRGPRD nociceptors in cutaneous C-fibers does not affect formalin-induced nocifensive behaviour.
Species:  Mouse
Tissue:  Spinal cord
Technique:  Genetic ablation
References:  17
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

Click here to show/hide data

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 [3,13]. MRGPRD+ neurons display nociceptor-like properties: long-duration action potentials, tetradotoxin-resistant Na+ current, and Ca2+ currents that are inhibited by mu opiods [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 [8,10] 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 [11,20].
Available Assays
DiscoveRx PathHunter® CHO-K1 MRGPRD (Orphan) High Expression β-Arrestin Cell Line Human Cat No. 93-0542C2A
DiscoveRx PathHunter® eXpress MRGPRD CHO-K1 β-Arrestin (Orphan) GPCR Assay Human Cat No. 93-0542E2ACP2

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. 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. 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. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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. and Hinuma, S. (2004) Identification of a G protein-coupled receptor specifically responsive to beta-alanine. J Biol Chem, 279: 23559-23564. [PMID:15037633]

19. 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]

20. 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]

21. 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]

22. 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]

To cite this database page, please use the following:

Wen Chiy Liew.
Class A Orphans: MRGPRD. Last modified on 14/12/2012. Accessed on 25/05/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=152.


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