MRGPRD

Summary

MRGPRD (MAS related GPR family member D, HGNC:29626) is a protein-coding gene on chromosome 11q13.3, encoding Mas-related G-protein coupled receptor member D (Q8TDS7). G protein-coupled receptor that acts as a mediator of peripheral pain and itch sensations.

Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Located in extracellular space.

Source: NCBI Gene 116512 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 65 total
• Druggable target: yes
• MANE Select transcript: NM_198923

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29626
Approved symbol	MRGPRD
Name	MAS related GPR family member D
Location	11q13.3
Locus type	gene with protein product
Status	Approved
Aliases	mrgD
Ensembl gene	ENSG00000172938
Ensembl biotype	protein_coding
OMIM	607231
Entrez	116512

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000309106

RefSeq mRNA: 1 — MANE Select: NM_198923 NM_198923

CCDS: CCDS31625

Canonical transcript exons

ENST00000309106 — 1 exons

Exon	Start	End
ENSE00001200401	68980021	68980986

Expression profiles

Bgee: expression breadth broad, 53 present calls, max score 83.14.

Top tissues by expression

114 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.14	silver quality
mucosa of stomach	UBERON:0001199	62.58	gold quality
muscle layer of sigmoid colon	UBERON:0035805	54.67	gold quality
left uterine tube	UBERON:0001303	52.55	gold quality
popliteal artery	UBERON:0002250	52.07	gold quality
tibial artery	UBERON:0007610	52.02	gold quality
right coronary artery	UBERON:0001625	51.31	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	49.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	49.53	gold quality
lower esophagus	UBERON:0013473	49.41	gold quality
cerebellum	UBERON:0002037	47.35	gold quality
smooth muscle tissue	UBERON:0001135	47.23	gold quality
cerebellar cortex	UBERON:0002129	47.19	gold quality
cerebellar hemisphere	UBERON:0002245	47.16	gold quality
ectocervix	UBERON:0012249	46.01	gold quality
right hemisphere of cerebellum	UBERON:0014890	45.45	silver quality
colon	UBERON:0001155	44.52	gold quality
body of uterus	UBERON:0009853	44.03	gold quality
urinary bladder	UBERON:0001255	43.90	gold quality
ascending aorta	UBERON:0001496	43.75	gold quality
thoracic aorta	UBERON:0001515	43.51	gold quality
granulocyte	CL:0000094	42.86	silver quality
myometrium	UBERON:0001296	42.50	gold quality
uterine cervix	UBERON:0000002	42.32	gold quality
descending thoracic aorta	UBERON:0002345	42.32	gold quality
sural nerve	UBERON:0015488	41.74	gold quality
right uterine tube	UBERON:0001302	41.38	silver quality
intestine	UBERON:0000160	40.85	gold quality
endocervix	UBERON:0000458	40.31	gold quality
left coronary artery	UBERON:0001626	39.81	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.65

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 6)

• Mas, MrgD, and MRG mediated Ang IV-stimulated AA release that was highest for Mas. While Ang III activated Mas and MrgX2, Ang II stimulated AA release via Mas and MRG. (PMID:18636314)
• MRGD could be involved in tumorigenesis and could also be a novel anticancer drug target. (PMID:22715397)
• Heptapeptide alamandine acts through Mas-related G-protein-coupled receptor member D producing physiological actions that resemble those generated by angiotensin-1-7. (PMID:23446738)
• Pruriception and neuronal coding in nociceptor subtypes in human and nonhuman primates. (PMID:33891544)
• Constitutive, Basal, and beta-Alanine-Mediated Activation of the Human Mas-Related G Protein-Coupled Receptor D Induces Release of the Inflammatory Cytokine IL-6 and Is Dependent on NF-kappaB Signaling. (PMID:34948051)
• The Expression of Alamandine Receptor MrgD in Clear Cell Renal Cell Carcinoma Is Associated with a Worse Prognosis and Unfavorable Response to Antiangiogenic Therapy. (PMID:38338778)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mrgprd	ENSMUSG00000051207
rattus_norvegicus	Mrgprd	ENSRNOG00000013448

Paralogs (10): MAS1 (ENSG00000130368), MRGPRX1 (ENSG00000170255), MRGPRF (ENSG00000172935), GPR152 (ENSG00000175514), MRGPRX4 (ENSG00000179817), MRGPRX3 (ENSG00000179826), MRGPRG (ENSG00000182170), MRGPRX2 (ENSG00000183695), MRGPRE (ENSG00000184350), MAS1L (ENSG00000204687)

Protein

Protein identifiers

Mas-related G-protein coupled receptor member D — Q8TDS7 (reviewed: Q8TDS7)

Alternative names: Beta-alanine receptor, G-protein coupled receptor TGR7

All UniProt accessions (1): Q8TDS7

UniProt curated annotations — full annotation on UniProt →

Function. G protein-coupled receptor that acts as a mediator of peripheral pain and itch sensations. Activated by various ligands, such as beta-alanine, beta-aminoisobutyrate, angiotensin 1-7, alamandine and allantoin, causing a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors. MRGPRD is both coupled to G(q) and G(i) G proteins: G(q) coupling activates phospholipase C-beta, releasing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) second messengers, while G(i) coupling mediates inhibition of adenylate cyclase activity. MRGPRD is specifically expressed in neurons that innervate the epidermis and acts as a key mediator of skin stimuli, such as itch, pain and mechanical stimuli. Required to maintain skin homeostasis in response to irritant dermatitis by initiating a signaling that promotes glutamate release, inhibiting mast cell hyperresponsiveness and skin inflammation. Required to prevent cardiomyocyte hypertrophy following activation by alamandine, a decarboxylation product of angiotensin 1-7. Acts as a receptor for allantoin in dorsal root ganglion neurons, eliciting chronic itch (pruritus).

Subcellular location. Cell membrane.

Activity regulation. Activated by diethylstilbestrol, a synthetic estrogen hormone.

Similarity. Belongs to the G-protein coupled receptor 1 family. Mas subfamily.

RefSeq proteins (1): NP_944605* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR026232	MRGPCRD	Family
IPR026234	MRGPCRFAMILY	Family

Pfam: PF00001

UniProt features (56 total): mutagenesis site 13, helix 9, topological domain 8, transmembrane region 7, turn 5, binding site 4, glycosylation site 4, strand 3, chain 1, region of interest 1, disulfide bond 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7Y15	ELECTRON MICROSCOPY	2.9
9DQJ	ELECTRON MICROSCOPY	2.9
9DQH	ELECTRON MICROSCOPY	2.92
7Y12	ELECTRON MICROSCOPY	3.1
7Y13	ELECTRON MICROSCOPY	3.1
7Y14	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDS7-F1	85.31	0.53

Antibody-complex structures (SAbDab): 2 — 7Y12, 7Y15

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 103; 179; 241; 245

Disulfide bonds (1): 164–175

Glycosylation sites (4): 2, 6, 16, 92

Mutagenesis-validated functional residues (13):

Position	Phenotype
102	does not affect g protein-coupled receptor signaling.
103	abolished g protein-coupled receptor signaling.
106	decreased g(i)- and g(q)-mediated signaling.
109	decreased g(i)-mediated signaling.
157	slightly increased g protein-coupled receptor signaling.
179	abolished g protein-coupled receptor signaling.
182	slightly increased g protein-coupled receptor signaling.
234	decreased g(i)-mediated signaling.
237	decreased g(i)-mediated signaling.
241	abolished g protein-coupled receptor signaling. abolished g(i)- and g(q)-mediated signaling.
242	abolished g(i)- and g(q)-mediated signaling.
245	decreased g protein-coupled receptor signaling.
246	abolished g protein-coupled receptor signaling.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors

MSigDB gene sets: 47 (showing top): GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, chr11q13, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, GOBP_MUSCLE_ADAPTATION, GOBP_VASODILATION, GOBP_REGULATION_OF_MUSCLE_HYPERTROPHY, GOBP_NEGATIVE_REGULATION_OF_BLOOD_PRESSURE, GOBP_REGULATION_OF_SYSTEM_PROCESS, GOMF_PEPTIDE_RECEPTOR_ACTIVITY

GO Biological Process (8): angiotensin-mediated vasodilation involved in regulation of systemic arterial blood pressure (GO:0002033), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), negative regulation of cardiac muscle hypertrophy (GO:0010614), sensory perception of itch (GO:0160025), signal transduction (GO:0007165)

GO Molecular Function (2): G protein-coupled receptor activity (GO:0004930), G protein-coupled peptide receptor activity (GO:0008528)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	2
G protein-coupled receptor signaling pathway	2
maintenance of blood vessel diameter homeostasis by renin-angiotensin	1
negative regulation of systemic arterial blood pressure	1
vasodilation	1
signal transduction	1
adenylate cyclase activator activity	1
adenylate cyclase inhibitor activity	1
phospholipase C activator activity	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
negative regulation of muscle hypertrophy	1
sensory perception	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
peptide receptor activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

574 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MRGPRD	NPFF	O15130	864
MRGPRD	TRPV1	Q8NER1	719
MRGPRD	TRPA1	O75762	698
MRGPRD	TRPM8	Q7Z2W7	651
MRGPRD	P2RX3	P56373	611
MRGPRD	SCN10A	Q9Y5Y9	596
MRGPRD	ACE2	Q9BYF1	588
MRGPRD	CALCA	P01258	582
MRGPRD	LNP1	A1A4G5	570
MRGPRD	AGT	P01019	570
MRGPRD	REN	P00797	542
MRGPRD	SLC17A8	Q8NDX2	542
MRGPRD	PIEZO2	Q9H5I5	521
MRGPRD	LPAR5	Q9H1C0	516
MRGPRD	AGTR1	P30556	514

IntAct

4 interactions, top by confidence:

A	B	Type	Score
RAMP1	MRGPRD	psi-mi:“MI:0915”(physical association)	0.400
MRGPRD	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
MRGPRD	RAMP3	psi-mi:“MI:0915”(physical association)	0.400

ESM2 similar proteins: P04201, P12526, P23749, P30554, P35410, P59534, P59535, Q3KNA1, Q3UG50, Q3UG61, Q4VHE7, Q645S5, Q645U4, Q645Y7, Q645Y8, Q645Y9, Q646A9, Q646B0, Q646C8, Q646D3, Q646F0, Q646F1, Q67ER9, Q67ES7, Q67ET0, Q67ET2, Q7TN38, Q7TN41, Q7TN44, Q7TN51, Q7TQA5, Q7TQA6, Q7TQB8, Q8CIP3, Q8R4G1, Q8TDS7, Q8VCJ6, Q91WW2, Q91WW3, Q91ZB8

Diamond homologs: A4FUQ5, B1PHQ8, B9VR26, E9QJ73, O08726, O08790, O35786, O42179, O70129, O88536, O88634, O88680, O88854, O97571, P0C7U4, P0C7U5, P21109, P21462, P21730, P25024, P25025, P25089, P25090, P30680, P30874, P30875, P30992, P30993, P32299, P32303, P33766, P34993, P34994, P35343, P35344, P35407, P35414, P46090, P46091, P49681

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MRGPRD	down-regulates	Inflammation
MRGPRD	down-regulates	Fibrosis
Alamandine	“up-regulates activity”	MRGPRD	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

65 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

174 predictions. Top by Δscore:

Variant	Effect	Δscore
11:68980587:TGA:T	donor_gain	0.9700
11:68980692:CGTGG:C	donor_gain	0.7000
11:68980320:C:CT	donor_gain	0.6500
11:68980321:C:CT	donor_gain	0.6500
11:68980187:A:AC	donor_gain	0.6400
11:68980188:C:CC	donor_gain	0.6400
11:68980188:CGGA:C	donor_gain	0.6400
11:68980569:G:A	donor_gain	0.6300
11:68980655:A:AC	donor_gain	0.6200
11:68980656:C:CC	donor_gain	0.6200
11:68980694:TGG:T	donor_gain	0.5900
11:68980067:T:TA	donor_gain	0.5700
11:68980586:TTG:T	donor_gain	0.5600
11:68980153:C:CT	acceptor_gain	0.5200
11:68980251:A:T	acceptor_gain	0.5100
11:68980250:CAG:C	acceptor_gain	0.5000
11:68980472:T:TA	donor_gain	0.4900
11:68980222:G:T	donor_gain	0.4700
11:68980492:G:A	donor_gain	0.4700
11:68980185:T:C	acceptor_gain	0.4600
11:68980277:AGAGG:A	donor_gain	0.4600
11:68980673:A:C	donor_gain	0.4500
11:68980275:T:TG	acceptor_gain	0.4400
11:68980406:A:AC	donor_gain	0.4400
11:68980249:CCAG:C	acceptor_gain	0.4300
11:68980262:A:T	donor_gain	0.4300
11:68980668:A:AC	donor_gain	0.4200
11:68980469:T:C	donor_gain	0.4100
11:68980147:G:A	donor_gain	0.4000
11:68980188:CGG:C	donor_gain	0.4000

AlphaMissense

2089 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:68980393:G:C	S198R	0.978
11:68980393:G:T	S198R	0.978
11:68980395:T:G	S198R	0.978
11:68980297:G:C	F230L	0.977
11:68980297:G:T	F230L	0.977
11:68980299:A:G	F230L	0.977
11:68980627:G:C	S120R	0.965
11:68980627:G:T	S120R	0.965
11:68980629:T:G	S120R	0.965
11:68980177:G:C	S270R	0.958
11:68980177:G:T	S270R	0.958
11:68980179:T:G	S270R	0.958
11:68980645:G:C	S114R	0.950
11:68980645:G:T	S114R	0.950
11:68980647:T:G	S114R	0.950
11:68980183:G:C	S268R	0.944
11:68980183:G:T	S268R	0.944
11:68980185:T:G	S268R	0.944
11:68980762:G:C	F75L	0.935
11:68980762:G:T	F75L	0.935
11:68980764:A:G	F75L	0.935
11:68980786:G:C	N67K	0.935
11:68980786:G:T	N67K	0.935
11:68980180:G:C	S269R	0.924
11:68980180:G:T	S269R	0.924
11:68980182:T:G	S269R	0.924
11:68980539:A:G	W150R	0.922
11:68980539:A:T	W150R	0.922
11:68980753:G:C	S78R	0.922
11:68980753:G:T	S78R	0.922

dbSNP variants (sampled 300 via entrez): RS1000957464 (11:68982497 G>A), RS1001869825 (11:68981885 C>G), RS1002300932 (11:68981643 G>C), RS1002960083 (11:68979858 T>C), RS1003568580 (11:68980507 G>A), RS1003945631 (11:68980745 G>A,T), RS1004234232 (11:68980928 C>G), RS1004488991 (11:68980395 T>C), RS1006153806 (11:68981729 C>A), RS1006747526 (11:68982745 A>G), RS1007020600 (11:68981787 TA>T), RS1007400565 (11:68982061 A>G), RS1009184257 (11:68981303 T>C), RS1009236653 (11:68981575 T>A), RS1010668494 (11:68980800 T>C)

Disease associations

OMIM: gene MIM:607231 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523899 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Class A Orphans with emerging pharmacology

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
β-alanine	Full agonist	4.8	pEC50

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	2
2-palmitoylglycerol	increases expression	1
Atrazine	increases expression	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4883531	Binding	PRESTO-Tango GPCRome screening (MRGPRD)	Data for DCP probe UCSF924

Cellosaurus cell lines

2 cell lines: 2 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_H464	CHO-K1/MRGPRD/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KY45	PathHunter CHO-K1 MRGPRD beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.