GPR12

gene
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Also known as GPCR21PPP1R84

Summary

GPR12 (G protein-coupled receptor 12, HGNC:4466) is a protein-coding gene on chromosome 13q12.13, encoding G-protein coupled receptor 12 (P47775). Brain-specific G protein-coupled receptor involved in regulating diverse physiological processes including neurite outgrowth, meiotic arrest, and lipid and carbohydrate metabolism.

Predicted to enable G protein-coupled receptor activity. Predicted to be involved in adenylate cyclase-activating G protein-coupled receptor signaling pathway and regulation of metabolic process. Predicted to act upstream of or within G protein-coupled receptor signaling pathway and intracellular calcium ion homeostasis. Predicted to be located in membrane. Predicted to be active in cytoplasm and plasma membrane.

Source: NCBI Gene 2835 — RefSeq curated summary.

At a glance

  • GWAS associations: 4
  • Clinical variants (ClinVar): 36 total
  • Druggable target: yes
  • MANE Select transcript: NM_005288

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:4466
Approved symbolGPR12
NameG protein-coupled receptor 12
Location13q12.13
Locus typegene with protein product
StatusApproved
AliasesGPCR21, PPP1R84
Ensembl geneENSG00000132975
Ensembl biotypeprotein_coding
OMIM600752
Entrez2835

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000381436, ENST00000405846, ENST00000881746

RefSeq mRNA: 1 — MANE Select: NM_005288 NM_005288

CCDS: CCDS9319

Canonical transcript exons

ENST00000405846 — 2 exons

ExonStartEnd
ENSE000015544652675520026759842
ENSE000015554332676057926760786

Expression profiles

Bgee: expression breadth ubiquitous, 102 present calls, max score 96.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0667 / max 81.9065, expressed in 118 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter IDTPM avgSamples expressed
1364770.8110106
1364780.164476
1364760.091339

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
cortical plateUBERON:000534396.54gold quality
ganglionic eminenceUBERON:000402386.11gold quality
cerebellar hemisphereUBERON:000224580.46gold quality
cerebellar cortexUBERON:000212980.43gold quality
right hemisphere of cerebellumUBERON:001489079.48gold quality
cerebellumUBERON:000203778.96gold quality
nucleus accumbensUBERON:000188278.23gold quality
endometrium epitheliumUBERON:000481178.00gold quality
caudate nucleusUBERON:000187377.49gold quality
prefrontal cortexUBERON:000045177.41gold quality
putamenUBERON:000187476.99gold quality
embryoUBERON:000092276.80gold quality
Brodmann (1909) area 9UBERON:001354075.07gold quality
dorsolateral prefrontal cortexUBERON:000983474.64gold quality
triceps brachiiUBERON:000150973.70gold quality
gluteal muscleUBERON:000200073.69gold quality
neocortexUBERON:000195073.31gold quality
frontal cortexUBERON:000187073.26gold quality
cingulate cortexUBERON:000302773.17gold quality
anterior cingulate cortexUBERON:000983572.93gold quality
telencephalonUBERON:000189372.14gold quality
pancreatic ductal cellCL:000207972.07gold quality
right frontal lobeUBERON:000281072.06gold quality
cerebral cortexUBERON:000095671.90gold quality
skin of legUBERON:000151171.28gold quality
tibialis anteriorUBERON:000138570.86silver quality
olfactory bulbUBERON:000226470.77gold quality
brainUBERON:000095570.05gold quality
forebrainUBERON:000189069.62gold quality
central nervous systemUBERON:000101769.50gold quality

Single-cell (SCXA)

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

ExperimentMarker?Max mean expression
E-ANND-3yes2.93

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

145 targeting GPR12, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-3163100.0077.238605
HSA-MIR-4673100.0066.641490
HSA-MIR-4776-3P100.0068.731340
HSA-MIR-548C-3P99.9974.017587
HSA-MIR-34A-5P99.9971.211784
HSA-MIR-449A99.9971.051776
HSA-MIR-548P99.9872.253784
HSA-MIR-4645-5P99.9865.811284
HSA-MIR-103A-3P99.9869.141595
HSA-MIR-10799.9869.141595
HSA-MIR-433-3P99.9869.371203
HSA-MIR-548N99.9871.944170
HSA-MIR-569699.9872.364487
HSA-MIR-548AN99.9770.912817
HSA-MIR-314899.9775.066478
HSA-MIR-60799.9773.625593
HSA-MIR-34C-5P99.9770.451577
HSA-MIR-449B-5P99.9770.261580
HSA-MIR-1229-3P99.9766.49906
HSA-MIR-570-3P99.9672.414910
HSA-MIR-302E99.9670.742669
HSA-MIR-495-3P99.9672.814197
HSA-MIR-568899.9673.234504
HSA-MIR-548AA99.9670.643753
HSA-MIR-548AP-3P99.9670.643753
HSA-MIR-548T-3P99.9670.643753
HSA-MIR-548AJ-3P99.9673.385345
HSA-MIR-548X-3P99.9673.385345
HSA-MIR-590-3P99.9674.346478
HSA-MIR-391099.9571.132227

Literature-anchored findings (GeneRIF, showing 6)

  • control of gene expression in vascular endothelial cells in the presence of fluid shear stress and classifies it as a sphingosine 1-phosphate receptor (PMID:12649592)
  • GPR12 may play a role in cell proliferation and survival (PMID:22430950)
  • Since we have demonstrated that CBD is an inverse agonist for GPR12, this provides novel mechanism of action for CBD, and an initial chemical scaffold upon which highly potent and efficacious agents acting on GPR12 may be developed with the ultimate goal of blocking cancer metastasis. (PMID:28888984)
  • GPR12 inhibits migration and promotes apoptosis in esophageal cancer and hypopharyngeal cancer cells. (PMID:33742771)
  • Structural insight into the constitutive activity of human orphan receptor GPR12. (PMID:36593162)
  • Exosomal miR-105-5p derived from bladder cancer stem cells targets for GPR12 to promote the malignancy of bladder cancer. (PMID:37789353)

Cross-species orthologs

3 orthologs

OrganismSymbolGene ID
danio_reriogpr12ENSDARG00000062934
mus_musculusGpr12ENSMUSG00000041468
rattus_norvegicusGpr12ENSRNOG00000039832

Paralogs (18): LPAR2 (ENSG00000064547), CNR1 (ENSG00000118432), MC3R (ENSG00000124089), S1PR4 (ENSG00000125910), GPR6 (ENSG00000146360), GPR119 (ENSG00000147262), MC4R (ENSG00000166603), S1PR1 (ENSG00000170989), LPAR3 (ENSG00000171517), MC5R (ENSG00000176136), S1PR5 (ENSG00000180739), GPR3 (ENSG00000181773), MC2R (ENSG00000185231), CNR2 (ENSG00000188822), LPAR1 (ENSG00000198121), S1PR3 (ENSG00000213694), MC1R (ENSG00000258839), S1PR2 (ENSG00000267534)

Protein

Protein identifiers

G-protein coupled receptor 12P47775 (reviewed: P47775)

All UniProt accessions (2): A8K2F5, P47775

UniProt curated annotations — full annotation on UniProt →

Function. Brain-specific G protein-coupled receptor involved in regulating diverse physiological processes including neurite outgrowth, meiotic arrest, and lipid and carbohydrate metabolism. Functions as a receptor with constitutive G(s)-mediated signaling activity that stimulates cyclic AMP (cAMP) production. Also engages the G(i)/G(o) pathway, which counteracts the cAMP increase driven by G(s) activation. Additionally, two lipids sphingosylphosphorylcholine (SPC) and sphingosine-1-phosphate (S1P) may act as endogenous ligand and activate GPR12.

Subunit / interactions. Interacts with GNAS.

Subcellular location. Cell membrane.

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

RefSeq proteins (1): NP_005279* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR000276GPCR_RhodpsnFamily
IPR000599GPR12Family
IPR000723GPR_3/6/12_orphanFamily
IPR017452GPCR_Rhodpsn_7TMDomain

Pfam: PF00001

UniProt features (42 total): helix 13, topological domain 8, transmembrane region 7, mutagenesis site 4, modified residue 2, glycosylation site 2, strand 2, chain 1, lipid moiety-binding region 1, disulfide bond 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDBMethodResolution (Å)
7Y3GELECTRON MICROSCOPY2.77

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P47775-F184.370.60

Antibody-complex structures (SAbDab): 17Y3G

Functional residue map

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

Post-translational modifications (3): 330, 332, 317

Disulfide bonds (1): 181–188

Glycosylation sites (2): 8, 24

Mutagenesis-validated functional residues (4):

PositionPhenotype
47greatly decreased constitutive activity of gpr12.
181greatly decreased constitutive activity of gpr12.
188greatly decreased constitutive activity of gpr12.
284greatly decreased constitutive activity of gpr12.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 128 (showing top): FXR_IR1_Q6, BENPORATH_ES_WITH_H3K27ME3, XU_GH1_AUTOCRINE_TARGETS_UP, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, SANSOM_APC_TARGETS_DN, GOBP_MONOATOMIC_ION_HOMEOSTASIS, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, JACKSON_DNMT1_TARGETS_UP, AP2_Q6_01, NKX3A_01, SHEN_SMARCA2_TARGETS_DN, GOBP_HOMEOSTATIC_PROCESS, GOBP_CHEMICAL_HOMEOSTASIS, GOBP_ADENYLATE_CYCLASE_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (4): intracellular calcium ion homeostasis (GO:0006874), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), signal transduction (GO:0007165)

GO Molecular Function (2): G protein-coupled receptor activity (GO:0004930), phosphatidylcholine binding (GO:0031210)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure2
intracellular monoatomic cation homeostasis1
calcium ion homeostasis1
G protein-coupled receptor activity1
signal transduction1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway1
adenylate cyclase activator activity1
cell communication1
cellular process1
signaling1
regulation of cellular process1
cellular response to stimulus1
transmembrane signaling receptor activity1
G protein-coupled receptor signaling pathway1
phospholipid binding1
cation binding1
quaternary ammonium group binding1
intracellular anatomical structure1
membrane1
cell periphery1

Protein interactions and networks

STRING

638 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
GPR12GPR55Q9Y2T6690
GPR12GPR18Q14330658
GPR12LRRC61Q9BV99528
GPR12TRPV2Q9Y5S1486
GPR12TRPM8Q7Z2W7470
GPR12GPR4P46093466
GPR12GPR31O00270464
GPR12TRPV3Q8NET8434
GPR12GPR139Q6DWJ6428
GPR12TRPA1O75762426
GPR12PDE3AQ14432424
GPR12TRPV1Q8NER1409
GPR12GPR35Q9HC97402
GPR12GPR21Q99679390
GPR12GPR22Q99680379
GPR12ALDH18A1P54886379

IntAct

130 interactions, top by confidence:

ABTypeScore
PPP1CAGPR12psi-mi:“MI:0407”(direct interaction)0.440
GPR12PDZD2psi-mi:“MI:0407”(direct interaction)0.440
PATJGPR12psi-mi:“MI:0407”(direct interaction)0.440
GPR12DLG3psi-mi:“MI:0407”(direct interaction)0.440
GPR12SYNJ2BPpsi-mi:“MI:0407”(direct interaction)0.440
GPR12APBA1psi-mi:“MI:0407”(direct interaction)0.440
MPDZGPR12psi-mi:“MI:0407”(direct interaction)0.440
GPR12TIAM2psi-mi:“MI:0407”(direct interaction)0.440
GPR12PICK1psi-mi:“MI:0407”(direct interaction)0.440
GPR12PTPN3psi-mi:“MI:0407”(direct interaction)0.440
GPR12DLG4psi-mi:“MI:0407”(direct interaction)0.440
GPR12APBA3psi-mi:“MI:0407”(direct interaction)0.440
GPR12MPP2psi-mi:“MI:0407”(direct interaction)0.440
GPR12PDZRN4psi-mi:“MI:0407”(direct interaction)0.440
GPR12LDB3psi-mi:“MI:0407”(direct interaction)0.440
GPR12NHERF4psi-mi:“MI:0407”(direct interaction)0.440
GPR12SNX27psi-mi:“MI:0407”(direct interaction)0.440
GPR12GOPCpsi-mi:“MI:0407”(direct interaction)0.440
GPR12ARHGAP21psi-mi:“MI:0407”(direct interaction)0.440
GPR12NHERF2psi-mi:“MI:0407”(direct interaction)0.440
GPR12SNTG1psi-mi:“MI:0407”(direct interaction)0.440
GPR12SNTG2psi-mi:“MI:0407”(direct interaction)0.440
GPR12RHPN1psi-mi:“MI:0407”(direct interaction)0.440
GPR12FRMPD4psi-mi:“MI:0407”(direct interaction)0.440
GPR12AHNAKpsi-mi:“MI:0407”(direct interaction)0.440
GPR12IL16psi-mi:“MI:0407”(direct interaction)0.440

BioGRID (93): ABCD1 (Affinity Capture-MS), SLC7A2 (Affinity Capture-MS), SLC16A13 (Affinity Capture-MS), TAP1 (Affinity Capture-MS), SLC35G2 (Affinity Capture-MS), MFSD9 (Affinity Capture-MS), CDC6 (Affinity Capture-MS), TFB2M (Affinity Capture-MS), PANX1 (Affinity Capture-MS), BTAF1 (Affinity Capture-MS), SLC29A1 (Affinity Capture-MS), SURF1 (Affinity Capture-MS), DGAT1 (Affinity Capture-MS), SLC2A12 (Affinity Capture-MS), PARL (Affinity Capture-MS)

ESM2 similar proteins: A5A4K9, A5A4L1, O02667, O08725, P0DMS8, P11616, P25099, P28190, P28647, P30542, P30731, P32304, P32305, P34970, P35342, P47745, P47775, P49892, P50407, P60893, P60894, P60895, Q0VC81, Q28309, Q5E9H8, Q5QD04, Q5RBG7, Q5RF57, Q60612, Q61618, Q6PI62, Q8BZA7, Q8VHD7, Q91559, Q923X8, Q923Y1, Q923Y2, Q923Y6, Q92847, Q95254

Diamond homologs: B0V1P1, O02777, O08530, O19037, O77616, O95136, O95977, P21453, P32244, P33033, P35413, P41968, P46089, P46095, P46628, P47752, P47775, P47798, P48303, P51651, P52592, P55167, P56442, P56443, P56444, P56445, P56446, P56447, P56448, P61793, P61794, Q01727, Q28031, Q29154, Q5E9P3, Q684M3, Q6A155, Q6YNI2, Q80SS9, Q80SZ5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

PathwayPartnersFoldFDR
Assembly and cell surface presentation of NMDA receptors836.9×3e-09
Neurexins and neuroligins932.2×1e-09
Protein-protein interactions at synapses629.0×3e-06
RHOA GTPase cycle56.8×7e-03

GO biological processes:

GO termPartnersFoldFDR
establishment or maintenance of epithelial cell apical/basal polarity965.4×4e-12
protein localization to synapse547.9×6e-06
receptor clustering646.8×7e-07
regulation of postsynaptic membrane neurotransmitter receptor levels531.0×4e-05
protein-containing complex assembly912.8×6e-06
cell-cell adhesion911.4×8e-06
protein localization to plasma membrane810.9×5e-05
regulation of small GTPase mediated signal transduction59.0×4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance31
Likely benign0
Benign4

Top pathogenic / likely-pathogenic (0)

SpliceAI

321 predictions. Top by Δscore:

VariantEffectΔscore
13:26760616:T:TAdonor_gain0.9800
13:26760607:T:TAdonor_gain0.9500
13:26758675:T:Cdonor_gain0.9400
13:26758670:A:Cdonor_gain0.9300
13:26760573:GGTCA:Gdonor_loss0.9300
13:26760574:GTCA:Gdonor_loss0.9300
13:26760575:TCA:Tdonor_loss0.9300
13:26760576:CA:Cdonor_loss0.9300
13:26760577:A:ATdonor_loss0.9300
13:26760578:C:CGdonor_loss0.9300
13:26760587:G:Adonor_gain0.9200
13:26759843:C:Gacceptor_gain0.9100
13:26759843:C:CCacceptor_gain0.9000
13:26759839:TCCTC:Tacceptor_gain0.8900
13:26759838:GTCCT:Gacceptor_gain0.8800
13:26759841:CT:Cacceptor_gain0.8800
13:26759902:A:Cacceptor_gain0.8800
13:26760579:C:Gdonor_loss0.8800
13:26759849:C:CTacceptor_gain0.8700
13:26759840:CCTCT:Cacceptor_gain0.8500
13:26759841:CTCTT:Cacceptor_gain0.8500
13:26759839:TCCT:Tacceptor_gain0.8400
13:26759840:CCTC:Cacceptor_gain0.8400
13:26759439:C:CCacceptor_gain0.8200
13:26759840:CCT:Cacceptor_gain0.8200
13:26759841:CTC:Cacceptor_gain0.8200
13:26759842:TCT:Tacceptor_gain0.8200
13:26759901:CA:Cacceptor_gain0.7900
13:26760580:T:Cdonor_loss0.7800
13:26760604:T:TAdonor_gain0.7800

AlphaMissense

2148 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
13:26759573:G:CS85R1.000
13:26759573:G:TS85R1.000
13:26759575:T:GS85R1.000
13:26759038:A:GW264R0.999
13:26759038:A:TW264R0.999
13:26759415:C:GR138P0.999
13:26759438:G:CS130R0.999
13:26759438:G:TS130R0.999
13:26759440:T:GS130R0.999
13:26759547:C:TG94D0.999
13:26759548:C:GG94R0.999
13:26759559:T:AD90V0.999
13:26759559:T:CD90G0.999
13:26759559:T:GD90A0.999
13:26759642:A:CN62K0.999
13:26759642:A:TN62K0.999
13:26759664:C:TG55E0.999
13:26759665:C:GG55R0.999
13:26759665:C:TG55R0.999
13:26758929:A:TI300K0.998
13:26758937:G:CN297K0.998
13:26758937:G:TN297K0.998
13:26758959:G:TA290D0.998
13:26759031:G:CP266R0.998
13:26759048:A:CF260L0.998
13:26759048:A:TF260L0.998
13:26759050:A:GF260L0.998
13:26759314:C:GG172R0.998
13:26759314:C:TG172R0.998
13:26759335:A:GW165R0.998

dbSNP variants (sampled 300 via entrez): RS1000391828 (13:26758392 A>G,T), RS1000655373 (13:26762066 C>A,G,T), RS1001138668 (13:26760317 C>G,T), RS1001179595 (13:26761826 G>A,C), RS1001573418 (13:26754986 G>A), RS1001698165 (13:26760935 G>A,T), RS1003114152 (13:26754802 G>T), RS1003514515 (13:26762536 A>G), RS1003578881 (13:26762308 A>T), RS1003701660 (13:26757854 A>AT), RS1003732638 (13:26757593 G>T), RS1004197874 (13:26755259 A>G), RS1004347306 (13:26757352 T>C), RS1004741136 (13:26756387 T>C), RS1005187082 (13:26761469 A>G)

Disease associations

OMIM: gene MIM:600752 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

StudyTraitp-value
GCST003817_11Mortality in sepsis1.000000e-06
GCST006110_19Nose morphology5.000000e-06
GCST010988_461Adult body size4.000000e-09
GCST90027899_10Eosinophilic esophagitis3.000000e-09

EFO canonical traits (1, from GWAS)

EFO IDTrait name
EFO:0004352mortality

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5006 (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:

LigandActionAffinityParameter
sphingosylphosphorylcholineFull agonist7.49pEC50
sphingosine 1-phosphateFull agonist6.97pEC50

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

ChemicalActions (top 5)PubMed papers
CGP 52608affects binding, increases reaction1
Benzo(a)pyreneincreases methylation1
Nickeldecreases expression1
Phthalic Acidsdecreases methylation1
Thiramincreases expression1
Okadaic Aciddecreases expression1
Copper Sulfateincreases expression1

ChEMBL screening assays

4 unique, capped per target: 2 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL4883402BindingPRESTO-Tango GPCRome screening (GPR12)Data for DCP probe UCSF924
CHEMBL5366029FunctionalAgonist activity at human GPR12 expressed in HEK293 cells assessed as increase in cAMP accumulation at 10 uM incubated for 30 mins by HTRF assayThe development of diphenyleneiodonium analogs as GPR3 agonists. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

CellosaurusNameCategorySex
CVCL_KX24PathHunter CHO-K1 GPR12 beta-arrestinSpontaneously immortalized cell lineFemale

Clinical trials (associated diseases)

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

  • Disease cohort memberships (association, not causation — diseases whose associated-gene cohort lists this gene; a subset are also under Associated diseases): eosinophilic esophagitis