GPR31

Summary

GPR31 (G protein-coupled receptor 31, HGNC:4486) is a protein-coding gene on chromosome 6q27, encoding 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid receptor (O00270). High-affinity receptor for 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-S-HETE), with much lower affinities for other HETE isomers. 12-S-HETE is a eicosanoid, a 12-lipoxygenase (ALOX12) metabolite of arachidonic acid, involved in many physiologic and pathologic processes.….

Enables G protein-coupled receptor activity and arachidonate binding activity. Involved in G protein-coupled receptor signaling pathway and response to acidic pH. Located in plasma membrane.

Source: NCBI Gene 2853 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 65 total — 2 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005299

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4486
Approved symbol	GPR31
Name	G protein-coupled receptor 31
Location	6q27
Locus type	gene with protein product
Status	Approved
Aliases	HETER1, 12-HETER
Ensembl gene	ENSG00000120436
Ensembl biotype	protein_coding
OMIM	602043
Entrez	2853

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000366834

RefSeq mRNA: 1 — MANE Select: NM_005299 NM_005299

CCDS: CCDS5299

Canonical transcript exons

ENST00000366834 — 1 exons

Exon	Start	End
ENSE00001442718	167155247	167157980

Expression profiles

Bgee: expression breadth broad, 12 present calls, max score 72.98.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelium of bronchus	UBERON:0002031	72.98	gold quality
thymus	UBERON:0002370	71.35	silver quality
vastus lateralis	UBERON:0001379	59.82	gold quality
quadriceps femoris	UBERON:0001377	59.78	gold quality
lymph node	UBERON:0000029	58.60	gold quality
cerebellar vermis	UBERON:0004720	57.59	gold quality
metanephric glomerulus	UBERON:0004736	55.97	gold quality
endometrium epithelium	UBERON:0004811	53.84	gold quality
vermiform appendix	UBERON:0001154	52.30	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
duodenum	UBERON:0002114	49.19	gold quality
colonic epithelium	UBERON:0000397	45.36	gold quality
tonsil	UBERON:0002372	43.84	gold quality
gall bladder	UBERON:0002110	40.41	silver quality
sural nerve	UBERON:0015488	39.86	gold quality
bone marrow cell	CL:0002092	38.01	gold quality
rectum	UBERON:0001052	37.48	silver quality
ganglionic eminence	UBERON:0004023	37.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	36.79	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
skeletal muscle tissue	UBERON:0001134	35.82	gold quality
muscle tissue	UBERON:0002385	35.26	gold quality
right uterine tube	UBERON:0001302	35.20	gold quality
mucosa of transverse colon	UBERON:0004991	35.04	gold quality
fallopian tube	UBERON:0003889	34.65	silver quality
spleen	UBERON:0002106	34.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.64

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 9)

• 12-HETER represents the first identified high affinity receptor for the 12-(S)-HETE hydroxyl fatty acids. (PMID:21712392)
• The data implicate 12-HETER1 in a critical new role in the regulation of prostate cancer progression and offer a novel alternative target for therapeutic intervention. (PMID:26965684)
• Suggest that GPR31 acts as a secretory pathway chaperone for KRAS4B in tumor cells. (PMID:28619714)
• this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE-GPR31 axis that functionally determines hepatic ischemia-reperfusion injury procession (PMID:29227475)
• High GPR31 expression levels were found to be correlated with pM classification of colorectal cancer (CRC) and to serve as an independent predictive factor of poor survival of CRC patients. (PMID:30416315)
• Telomere length correlates with subtelomeric DNA methylation in long-term mindfulness practitioners. (PMID:32165663)
• Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation. (PMID:33972436)
• Expression of Proton-Sensitive GPR31, GPR151, TASK1 and TASK3 in Common Skin Tumors. (PMID:35011589)
• The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells. (PMID:39432783)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gpr31b	ENSMUSG00000071311
rattus_norvegicus	Gpr31	ENSRNOG00000072725

Paralogs (15): GPR42 (ENSG00000126251), FFAR2 (ENSG00000126262), FFAR1 (ENSG00000126266), OXER1 (ENSG00000162881), OXGR1 (ENSG00000165621), P2RY1 (ENSG00000169860), P2RY6 (ENSG00000171631), GPR82 (ENSG00000171657), P2RY2 (ENSG00000175591), HCAR2 (ENSG00000182782), FFAR3 (ENSG00000185897), P2RY4 (ENSG00000186912), HCAR1 (ENSG00000196917), SUCNR1 (ENSG00000198829), HCAR3 (ENSG00000255398)

Protein

Protein identifiers

12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid receptor — O00270 (reviewed: O00270)

Alternative names: G-protein coupled receptor 31, GPR31/12-HETER

All UniProt accessions (1): O00270

UniProt curated annotations — full annotation on UniProt →

Function. High-affinity receptor for 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-S-HETE), with much lower affinities for other HETE isomers. 12-S-HETE is a eicosanoid, a 12-lipoxygenase (ALOX12) metabolite of arachidonic acid, involved in many physiologic and pathologic processes. 12-S-HETE-binding leads to activation of ERK1/2 (MAPK3/MAPK1), MEK, and NF-kappa-B pathways leading to cell growth. Plays a crucial role for proliferation, survival and macropinocytosis of KRAS-dependent cancer cells by mediating the translocation of KRAS from the endoplasmic reticulum to the plasma membrane (PM) and its association with the PM. Contributes to enhanced immune responses by inducing dendrite protrusion of small intestinal CX3CR1(+) phagocytes for the uptake of luminal antigens. Acts also as a key receptor for 12-(S)-HETE-mediated liver ischemia reperfusion injury. Proton-sensing G protein-coupled receptor.

Subunit / interactions. Interacts with KRAS; in a farnesylation-dependent manner.

Subcellular location. Cell membrane.

Induction. Up-regulated in prostate cancer.

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

RefSeq proteins (1): NP_005290* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR051893	HCARs	Family

Pfam: PF00001

UniProt features (20 total): topological domain 8, transmembrane region 7, sequence conflict 2, chain 1, glycosylation site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00270-F1	82.95	0.40

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 (1): 5

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-418594	G alpha (i) signalling events
R-HSA-444209	Free fatty acid receptors

MSigDB gene sets: 63 (showing top): GOBP_INFLAMMATORY_RESPONSE, GCM_PRKCG, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_RESPONSE_TO_ISCHEMIA, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_LIPID_METABOLIC_PROCESS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_RESPONSE_TO_PH, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE, GOBP_RESPONSE_TO_ACIDIC_PH, chr6q27

GO Biological Process (8): response to molecule of bacterial origin (GO:0002237), response to ischemia (GO:0002931), lipid metabolic process (GO:0006629), G protein-coupled receptor signaling pathway (GO:0007186), response to acidic pH (GO:0010447), negative regulation of inflammatory response (GO:0050728), positive regulation of immune response (GO:0050778), signal transduction (GO:0007165)

GO Molecular Function (4): G protein-coupled receptor activity (GO:0004930), bioactive lipid receptor activity (GO:0045125), arachidonate binding (GO:0050544), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR downstream signalling	1
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
response to bacterium	1
response to external biotic stimulus	1
response to stress	1
primary metabolic process	1
signal transduction	1
response to pH	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
positive regulation of immune system process	1
immune response	1
positive regulation of response to stimulus	1
regulation of immune response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
icosanoid binding	1
icosatetraenoic acid binding	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

482 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR31	ZIC3	O60481	841
GPR31	NODAL	Q96S42	760
GPR31	CFC1	P0CG37	719
GPR31	ACVR2B	Q13705	588
GPR31	DENR	O43583	549
GPR31	B9ZVM9	B9ZVM9	511
GPR31	GPR3	P46089	495
GPR31	GPR26	Q8NDV2	494
GPR31	GPR151	Q8TDV0	489
GPR31	GPR139	Q6DWJ6	478
GPR31	GPR12	P47775	464
GPR31	GPR75	O95800	457
GPR31	SMAD4	Q13485	453
GPR31	GPR39	O43194	447
GPR31	LTB4R2	Q9NPC1	439

IntAct

14 interactions, top by confidence:

A	B	Type	Score
KRAS	GPR31	psi-mi:“MI:0915”(physical association)	0.460
KRAS	GPR31	psi-mi:“MI:0403”(colocalization)	0.460
NRAS	GPR31	psi-mi:“MI:0915”(physical association)	0.400
HRAS	GPR31	psi-mi:“MI:0915”(physical association)	0.400
KRAS	GPR31	psi-mi:“MI:0915”(physical association)	0.400
GPR31	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP1	GPR31	psi-mi:“MI:0915”(physical association)	0.400
GPR31	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	GPR31	psi-mi:“MI:0915”(physical association)	0.400
GPR31	RAMP3	psi-mi:“MI:0915”(physical association)	0.400

ESM2 similar proteins: A0A0R4IM31, A0A0R4IP11, E9QJ73, F8VQN3, O00270, O00421, O15218, O35457, O97663, P31392, P32302, P34997, P43142, P49685, Q04683, Q0II78, Q0VDU3, Q149R9, Q16570, Q3ZC80, Q67ES2, Q6XKD3, Q75ZH0, Q7TMA4, Q7TQA9, Q7TQP4, Q7TSN5, Q7TSN6, Q863H8, Q8BZR0, Q8TDV2, Q95LF2, Q95LF3, Q95LF4, Q95LF5, Q95LF7, Q95LF9, Q95LG5, Q96CH1, Q96G91

Diamond homologs: A0A4W3GG95, A0A6I8PUB9, B2GV46, B5X337, D4A7K7, E7FEL0, E9QJ73, F8VQN3, O00270, O08726, O08858, O14842, O14843, O15529, O42179, O43603, O46685, O60755, O77408, O88410, O88626, O88634, O88853, P21109, P23944, P25024, P25025, P35344, P35383, P35414, P41231, P41232, P46092, P46093, P49652, P49682, P49683, P50132, P51675, P51679

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	56
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1807798	GRCh37/hg19 6q26-27(chr6:163181847-170919482)x1	Pathogenic
2685219	GRCh37/hg19 6q27(chr6:167091844-170919482)x1	Pathogenic

SpliceAI

8 predictions. Top by Δscore:

Variant	Effect	Δscore
6:167157296:T:TA	donor_gain	0.3000
6:167157342:TGTGG:T	donor_gain	0.2800
6:167156669:CT:C	acceptor_gain	0.2700
6:167157463:G:T	donor_gain	0.2400
6:167157469:AAG:A	donor_gain	0.2300
6:167157457:C:A	acceptor_gain	0.2200
6:167157488:CGGAG:C	donor_gain	0.2100
6:167157489:GGAGG:G	donor_gain	0.2100

AlphaMissense

2039 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:167157667:G:C	N55K	0.965
6:167157667:G:T	N55K	0.965
6:167157417:A:G	W139R	0.964
6:167157417:A:T	W139R	0.964
6:167157127:A:C	F235L	0.960
6:167157127:A:T	F235L	0.960
6:167157129:A:G	F235L	0.960
6:167157139:A:C	F231L	0.960
6:167157139:A:T	F231L	0.960
6:167157141:A:G	F231L	0.960
6:167156965:G:C	F289L	0.949
6:167156965:G:T	F289L	0.949
6:167156967:A:G	F289L	0.949
6:167157007:A:C	S275R	0.947
6:167157007:A:T	S275R	0.947
6:167157009:T:G	S275R	0.947
6:167157736:G:C	N32K	0.946
6:167157736:G:T	N32K	0.946
6:167157541:G:C	S97R	0.945
6:167157541:G:T	S97R	0.945
6:167157543:T:G	S97R	0.945
6:167156998:G:C	N278K	0.944
6:167156998:G:T	N278K	0.944
6:167157629:G:C	P68R	0.940
6:167157122:G:T	P237H	0.937
6:167157122:G:C	P237R	0.936
6:167157741:C:G	G31R	0.936
6:167157680:A:T	V51D	0.935
6:167157740:C:T	G31D	0.933
6:167157520:G:C	F104L	0.932

dbSNP variants (sampled 300 via entrez): RS1000021498 (6:167154786 G>T), RS1000279678 (6:167156762 G>T), RS1000474506 (6:167154926 A>G), RS1001611890 (6:167155550 C>T), RS1001678081 (6:167156056 C>A), RS1002002574 (6:167159923 C>A), RS1005056292 (6:167159013 G>A), RS1006916464 (6:167158327 T>A), RS1009150760 (6:167157644 A>C,G), RS1009921441 (6:167156088 G>A,T), RS1010053561 (6:167155402 C>T), RS1010643133 (6:167159489 A>C,G), RS1010734303 (6:167157979 A>G,T), RS1011812153 (6:167156594 CTT>C), RS1011976323 (6:167158039 G>A)

Disease associations

OMIM: gene MIM:602043 | 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
GCST002228_3	Social autistic-like traits	3.000000e-06
GCST002642_3	Response to simvastatin treatment (PCSK9 protein level change)	4.000000e-06
GCST003832_9	Asthma (childhood onset)	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005426	autism spectrum disorder symptom
EFO:0006899	PCSK9 protein measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523859 (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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
12S-HETE	Full agonist	9.55	pEC50
12S-[3H]HETE	Agonist	8.31	pKd

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Lipopolysaccharides	affects response to substance, affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Cyclosporine	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
CHEMBL4883445	Binding	PRESTO-Tango GPCRome screening (GPR31)	Data for DCP probe UCSF924

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KX57	PathHunter CHO-K1 GPR31 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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