GPR75

Summary

GPR75 (G protein-coupled receptor 75, HGNC:4526) is a protein-coding gene on chromosome 2p16.2, encoding Probable G-protein coupled receptor 75 (O95800). G protein-coupled receptor that is activated by the chemokine CCL5/RANTES.

GPR75 is a member of the G protein-coupled receptor family. GPRs are cell surface receptors that activate guanine-nucleotide binding proteins upon the binding of a ligand.

Source: NCBI Gene 10936 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 93 total
• Druggable target: yes
• MANE Select transcript: NM_006794

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4526
Approved symbol	GPR75
Name	G protein-coupled receptor 75
Location	2p16.2
Locus type	gene with protein product
Status	Approved
Aliases	WI-31133
Ensembl gene	ENSG00000119737
Ensembl biotype	protein_coding
OMIM	606704
Entrez	10936

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000394705

RefSeq mRNA: 1 — MANE Select: NM_006794 NM_006794

CCDS: CCDS1849

Canonical transcript exons

ENST00000394705 — 2 exons

Exon	Start	End
ENSE00001519289	53852912	53854865
ENSE00001519292	53859828	53859967

Expression profiles

Bgee: expression breadth ubiquitous, 157 present calls, max score 89.54.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9425 / max 116.5308, expressed in 254 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28360	2.9425	254

Top tissues by expression

247 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	89.54	gold quality
ventricular zone	UBERON:0003053	75.71	gold quality
islet of Langerhans	UBERON:0000006	74.46	gold quality
prefrontal cortex	UBERON:0000451	72.75	gold quality
medial globus pallidus	UBERON:0002477	72.52	gold quality
caudate nucleus	UBERON:0001873	71.85	gold quality
cortical plate	UBERON:0005343	71.85	gold quality
nucleus accumbens	UBERON:0001882	71.15	gold quality
amygdala	UBERON:0001876	71.10	gold quality
putamen	UBERON:0001874	70.19	gold quality
anterior cingulate cortex	UBERON:0009835	69.44	gold quality
right frontal lobe	UBERON:0002810	68.79	gold quality
corpus callosum	UBERON:0002336	68.15	gold quality
ganglionic eminence	UBERON:0004023	68.07	gold quality
Brodmann (1909) area 9	UBERON:0013540	67.94	gold quality
frontal cortex	UBERON:0001870	67.56	gold quality
neocortex	UBERON:0001950	67.55	gold quality
stromal cell of endometrium	CL:0002255	67.47	gold quality
hypothalamus	UBERON:0001898	66.95	gold quality
smooth muscle tissue	UBERON:0001135	66.76	gold quality
globus pallidus	UBERON:0001875	66.71	gold quality
left adrenal gland	UBERON:0001234	65.81	gold quality
forebrain	UBERON:0001890	65.66	gold quality
bone marrow cell	CL:0002092	65.65	silver quality
dorsolateral prefrontal cortex	UBERON:0009834	65.33	gold quality
pancreas	UBERON:0001264	65.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	65.26	gold quality
left adrenal gland cortex	UBERON:0035825	65.17	gold quality
brain	UBERON:0000955	64.84	gold quality
right adrenal gland	UBERON:0001233	64.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

28 targeting GPR75, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-1245B-3P	98.01	68.91	1387
HSA-MIR-6730-3P	97.03	67.54	889
HSA-MIR-4695-3P	96.71	67.21	836

Literature-anchored findings (GeneRIF, showing 5)

• This study explored the interaction of CCL5 with GPR75, an orphan receptor of the Gqalpha family of GPCRs, which appears to be expressed more abundantly in neuron-like cells than astrocytes. (PMID:29772059)
• Study results show for the first time the involvement of the 20-HETE-GPR75 receptor in the activation of intracellular signaling known to be stimulated in cell malignant transformations leading to the differentiation of PC-3 prostate cancer cells towards a more aggressive phenotype. GPR75 receptor stimulation is necessary for the pro-metastatic actions of 20-HETE in androgen insensitive prostate cancer cells. (PMID:31760076)
• Uncovering the signalling, structure and function of the 20-HETE-GPR75 pairing: Identifying the chemokine CCL5 as a negative regulator of GPR75. (PMID:33974269)
• Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. (PMID:34210852)
• G Protein-Coupled Receptor 75 (GPR75) As a Novel Molecule for Targeted Therapy of Cancer and Metabolic Syndrome. (PMID:37247305)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpr75	ENSDARG00000098526
mus_musculus	Gpr75	ENSMUSG00000043999
rattus_norvegicus	Gpr75	ENSRNOG00000022176

Paralogs (33): TACR2 (ENSG00000075073), PROKR2 (ENSG00000101292), GPR50 (ENSG00000102195), TACR1 (ENSG00000115353), PRLHR (ENSG00000119973), GPR83 (ENSG00000123901), MCHR1 (ENSG00000128285), OR11H1 (ENSG00000130538), MTNR1B (ENSG00000134640), MCHR2 (ENSG00000152034), NPY1R (ENSG00000164128), NPY5R (ENSG00000164129), MTNR1A (ENSG00000168412), PROKR1 (ENSG00000169618), TACR3 (ENSG00000169836), OR9G1 (ENSG00000174914), OR11H4 (ENSG00000176198), OR11H6 (ENSG00000176219), OR9A2 (ENSG00000179468), GPR88 (ENSG00000181656), GPR19 (ENSG00000183150), NPY2R (ENSG00000185149), OR11G2 (ENSG00000196832), NPY4R (ENSG00000204174), OR11A1 (ENSG00000204694), OR9A1P (ENSG00000237621), OR11H12 (ENSG00000257115), OR9A4 (ENSG00000258083), OR11H2 (ENSG00000258453), OR11H7 (ENSG00000258806), NPY4R2 (ENSG00000264717), OR10X1 (ENSG00000279111), OR51F1 (ENSG00000280021)

Protein

Protein identifiers

Probable G-protein coupled receptor 75 — O95800 (reviewed: O95800)

All UniProt accessions (1): O95800

UniProt curated annotations — full annotation on UniProt →

Function. G protein-coupled receptor that is activated by the chemokine CCL5/RANTES. Probably coupled to heterotrimeric Gq proteins, it stimulates inositol trisphosphate production and calcium mobilization upon activation. Together with CCL5/RANTES, may play a role in neuron survival through activation of a downstream signaling pathway involving the PI3, Akt and MAP kinases. CCL5/RANTES may also regulate insulin secretion by pancreatic islet cells through activation of this receptor.

Subcellular location. Cell membrane.

Tissue specificity. Expressed at high levels in brain and spinal cord and at detectable levels in retinal pigment epithelium. In situ hybridization of adult eye sections localized transcripts only to the perivascular cells, surrounding retinal arterioles, in the ganglion cell/nerve fiber layer. Also expressed by islet cells (at protein level).

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

RefSeq proteins (1): NP_006785* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (30 total): topological domain 8, transmembrane region 7, sequence variant 7, glycosylation site 3, sequence conflict 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9XQC	ELECTRON MICROSCOPY	3
9XQN	ELECTRON MICROSCOPY	3.91

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95800-F1	64.05	0.23

Functional residue map

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

Glycosylation sites (3): 2, 12, 25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 62 (showing top): GOBP_RESPONSE_TO_PEPTIDE, MODULE_289, SHEN_SMARCA2_TARGETS_DN, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_UP, GOMF_G_PROTEIN_COUPLED_CHEMOATTRACTANT_RECEPTOR_ACTIVITY, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, GOBP_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_CHEMOKINE, P53_DN.V2_DN, OISHI_CHOLANGIOMA_STEM_CELL_LIKE_UP, GOMF_IMMUNE_RECEPTOR_ACTIVITY, SIRT3_TARGET_GENES, MIR452_5P, MIR892C_3P

GO Biological Process (4): G protein-coupled receptor signaling pathway (GO:0007186), chemokine-mediated signaling pathway (GO:0070098), signal transduction (GO:0007165), ERK1 and ERK2 cascade (GO:0070371)

GO Molecular Function (2): G protein-coupled receptor activity (GO:0004930), C-C chemokine receptor activity (GO:0016493)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
G protein-coupled receptor activity	1
signal transduction	1
cytokine-mediated signaling pathway	1
cellular response to chemokine	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
MAPK cascade	1
transmembrane signaling receptor activity	1
chemokine receptor activity	1
C-C chemokine binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

436 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR75	CCL5	P13501	922
GPR75	GPR88	Q9GZN0	663
GPR75	ASB3	Q9Y575	647
GPR75	CHAC2	Q8WUX2	574
GPR75	FFAR1	O14842	573
GPR75	GPR176	Q14439	565
GPR75	VSTM5	A8MXK1	530
GPR75	GPR151	Q8TDV0	528
GPR75	CYP4F3	Q08477	522
GPR75	PSME4	Q14997	487
GPR75	CYP4A11	Q02928	468
GPR75	ARRB2	P32121	464
GPR75	ARRB1	P49407	463
GPR75	GPR31	O00270	457
GPR75	VDAC1	P21796	454

IntAct

0 interactions, top by confidence:

BioGRID (1): GPR75 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A2BGS3, A6NGA9, E7F594, O36364, O60478, O60883, O95800, O95838, P03208, P16849, P31389, P34590, P35367, P49219, Q03613, Q09351, Q09964, Q09965, Q14439, Q16950, Q16951, Q2KI97, Q3U3F9, Q5FVG1, Q5IXF8, Q5UAW9, Q60755, Q64017, Q66615, Q66H29, Q6P7G9, Q6SW98, Q6X632, Q7TSN5, Q7TSN6, Q80W35, Q80WT4, Q8BNQ3, Q8C206, Q8CIM5

Diamond homologs: O95800, Q6X632

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	83
Likely benign	5
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

285 predictions. Top by Δscore:

Variant	Effect	Δscore
2:53859822:TCTCA:T	donor_loss	0.9900
2:53859823:CTCA:C	donor_loss	0.9900
2:53859824:TCA:T	donor_loss	0.9900
2:53859825:CA:C	donor_loss	0.9900
2:53859826:A:AG	donor_loss	0.9900
2:53859827:CCT:C	donor_loss	0.9800
2:53859830:G:A	donor_gain	0.9800
2:53859826:ACCTG:A	donor_gain	0.9500
2:53859827:CCTG:C	donor_gain	0.9500
2:53859827:CCTGC:C	donor_gain	0.9500
2:53859826:A:AC	donor_gain	0.9400
2:53859827:C:CC	donor_gain	0.9400
2:53859854:T:TA	donor_gain	0.9300
2:53854835:A:C	acceptor_gain	0.9200
2:53854864:GCCT:G	acceptor_loss	0.9200
2:53854866:C:T	acceptor_loss	0.9200
2:53854867:T:G	acceptor_loss	0.9200
2:53854887:C:T	acceptor_gain	0.9200
2:53853250:CTGG:C	donor_gain	0.9000
2:53854866:C:CC	acceptor_gain	0.9000
2:53853013:A:C	donor_gain	0.8900
2:53853111:AAGAT:A	donor_gain	0.8900
2:53852987:G:T	donor_gain	0.8800
2:53854861:TAAGC:T	acceptor_gain	0.8800
2:53859820:CCTCT:C	donor_loss	0.8800
2:53859821:CTCTC:C	donor_loss	0.8800
2:53859686:C:A	donor_gain	0.8700
2:53859748:T:A	donor_gain	0.8700
2:53852986:TGA:T	donor_gain	0.8600
2:53854888:A:T	acceptor_gain	0.8600

AlphaMissense

3548 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:53854241:A:C	S172R	0.997
2:53854241:A:T	S172R	0.997
2:53854243:T:G	S172R	0.997
2:53854252:A:G	W169R	0.994
2:53854252:A:T	W169R	0.994
2:53854488:T:A	D90V	0.993
2:53854488:T:G	D90A	0.993
2:53854577:G:C	N60K	0.993
2:53854577:G:T	N60K	0.993
2:53854338:G:T	A140D	0.990
2:53854500:A:G	L86P	0.990
2:53854329:C:G	R143P	0.989
2:53853790:A:G	C323R	0.988
2:53854569:A:T	V63D	0.988
2:53853760:A:G	C333R	0.987
2:53854488:T:C	D90G	0.987
2:53854502:G:C	N85K	0.987
2:53854502:G:T	N85K	0.987
2:53854591:C:G	G56R	0.987
2:53854326:A:G	L144P	0.986
2:53854382:A:C	S125R	0.986
2:53854382:A:T	S125R	0.986
2:53854384:T:G	S125R	0.986
2:53854489:C:G	D90H	0.986
2:53853641:G:C	N372K	0.984
2:53853641:G:T	N372K	0.984
2:53854083:A:T	I225N	0.983
2:53854581:C:T	G59D	0.983
2:53853750:G:C	P336R	0.982
2:53853639:G:T	P373H	0.981

dbSNP variants (sampled 300 via entrez): RS1000066296 (2:53859651 A>T), RS1000286325 (2:53859808 A>G), RS1000484885 (2:53860097 C>G,T), RS1000703883 (2:53859064 A>G), RS1000847586 (2:53854194 A>G), RS1001068556 (2:53858366 T>C), RS1001495127 (2:53861365 T>C,G), RS1001514410 (2:53854857 C>G,T), RS1001762396 (2:53860339 C>T), RS1002272424 (2:53856034 C>A), RS1002912655 (2:53858727 T>G), RS1002943900 (2:53858464 T>A,C), RS1003114304 (2:53853068 T>C), RS1003246212 (2:53857380 G>A), RS1003274191 (2:53857238 A>C,G)

Disease associations

OMIM: gene MIM:606704 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006193_90	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-11
GCST006194_1	Diastolic blood pressure x smoking status (current vs non-current) interaction (1df test)	2.000000e-09
GCST010002_365	Refractive error	3.000000e-34

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523861 (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
CCL5	Full agonist	9.59	pEC50

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases expression, affects methylation	2
Estradiol	increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	affects cotreatment, decreases expression	1
Vehicle Emissions	affects methylation, increases abundance	1
Benzo(a)pyrene	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	affects expression	1
Niclosamide	decreases expression	1
Nitrogen Dioxide	affects methylation, increases abundance	1
Potassium Chloride	decreases response to substance, increases expression	1
Dronabinol	decreases response to substance, increases expression	1
Triclosan	decreases expression	1
Urethane	increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	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
CHEMBL4883466	Binding	PRESTO-Tango GPCRome screening (GPR75)	Data for DCP probe UCSF924

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 transformed cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9FT	Ubigene HEK293 GPR75 KO	Transformed cell line	Female
CVCL_E1YF	HAP1 GPR75 (-) 1	Cancer cell line	Male
CVCL_E1YG	HAP1 GPR75 (-) 2	Cancer cell line	Male
CVCL_E1YH	HAP1 GPR75 (-) 3	Cancer cell line	Male
CVCL_KX71	PathHunter CHO-K1 GPR75 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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