GPR78

Summary

GPR78 (G protein-coupled receptor 78, HGNC:4528) is a protein-coding gene on chromosome 4p16.1, encoding G-protein coupled receptor 78 (Q96P69). Orphan receptor.

The protein encoded by this gene belongs to the G protein-coupled receptor family, which contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins. This is an orphan receptor, which displays significant level of constitutive activity. Association analysis shows preliminary evidence for the involvement of this gene in susceptibility to bipolar affective disorder and schizophrenia. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 27201 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 103 total
• Druggable target: yes
• MANE Select transcript: NM_080819

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4528
Approved symbol	GPR78
Name	G protein-coupled receptor 78
Location	4p16.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000155269
Ensembl biotype	protein_coding
OMIM	606921
Entrez	27201

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding_CDS_not_defined, 1 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000382487, ENST00000503448, ENST00000503981, ENST00000504255, ENST00000509216, ENST00000513120, ENST00000514302

RefSeq mRNA: 1 — MANE Select: NM_080819 NM_080819

CCDS: CCDS3403

Canonical transcript exons

ENST00000382487 — 3 exons

Exon	Start	End
ENSE00001492278	8580392	8581650
ENSE00002026341	8587054	8590023
ENSE00003577738	8582531	8582644

Expression profiles

Bgee: expression breadth broad, 87 present calls, max score 85.15.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2402 / max 79.6596, expressed in 42 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46891	0.0572	14
46895	0.0559	17
46897	0.0531	10
46894	0.0478	9
46896	0.0262	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	85.15	gold quality
esophagus mucosa	UBERON:0002469	81.24	gold quality
left ovary	UBERON:0002119	79.95	gold quality
right ovary	UBERON:0002118	75.47	gold quality
ovary	UBERON:0000992	72.61	gold quality
vagina	UBERON:0000996	66.37	gold quality
stromal cell of endometrium	CL:0002255	65.00	gold quality
ectocervix	UBERON:0012249	62.88	gold quality
uterine cervix	UBERON:0000002	60.84	gold quality
esophagus	UBERON:0001043	60.15	gold quality
right uterine tube	UBERON:0001302	59.45	gold quality
endocervix	UBERON:0000458	58.57	gold quality
female reproductive system	UBERON:0000474	57.31	gold quality
skin of hip	UBERON:0001554	56.81	gold quality
gall bladder	UBERON:0002110	55.57	gold quality
prefrontal cortex	UBERON:0000451	55.25	gold quality
decidua	UBERON:0002450	55.16	gold quality
placenta	UBERON:0001987	52.14	gold quality
left uterine tube	UBERON:0001303	50.99	gold quality
upper leg skin	UBERON:0004262	50.64	silver quality
body of uterus	UBERON:0009853	50.11	gold quality
fallopian tube	UBERON:0003889	49.82	gold quality
sural nerve	UBERON:0015488	49.67	gold quality
urinary bladder	UBERON:0001255	49.62	gold quality
colonic epithelium	UBERON:0000397	49.38	gold quality
smooth muscle tissue	UBERON:0001135	49.16	gold quality
medial globus pallidus	UBERON:0002477	48.97	gold quality
frontal cortex	UBERON:0001870	48.26	gold quality
uterus	UBERON:0000995	48.21	gold quality
neocortex	UBERON:0001950	47.43	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	65.41
E-MTAB-6678	yes	6.35
E-ANND-3	yes	3.38

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

74 targeting GPR78, 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-4533	100.00	69.48	2758
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6883-5P	99.69	68.05	3785

Literature-anchored findings (GeneRIF, showing 6)

• Two haplotypes remained significant in both the female bipolar affective disorder individuals and in the full sample of affected female individuals. Results provide preliminary evidence for involvement of GPR78 in susceptibility to BPAD and SCZ. (PMID:16389273)
• Knockdown of GPR78 in lung cancer cells suppressed cell migration and GPR78 modulated the formation of actin stress fibers in A549 cells, in a RhoA- and Rac1-dependent manner. (PMID:27697106)
• We reveal distinct binding affinities between the binary and ternary complexes thus formed, that suggest a preference for the PERK signaling branch under stress, and a predilection for the GRP78-UPR sensor complex formation upon stressor removal. These results imply a gated UPR mechanism that tunes the overall cellular behavior to the accumulation of unfolded proteins. (PMID:28416388)
• rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. [Meta-analysis] (PMID:31413261)
• Association of G protein-coupled receptor 78 with salivary dysfunction in male Sjogren’s patients. (PMID:36652502)
• COLEC10 Induces Endoplasmic Reticulum Stress by Occupying GRP78 and Inhibits Hepatocellular Carcinoma. (PMID:36925047)

Cross-species orthologs

0 orthologs

Paralogs (3): GPR63 (ENSG00000112218), GPR45 (ENSG00000135973), GPR26 (ENSG00000154478)

Protein

Protein identifiers

G-protein coupled receptor 78 — Q96P69 (reviewed: Q96P69)

All UniProt accessions (3): Q96P69, B2R7M4, D6RB95

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor. Displays a significant level of constitutive activity. Its effect is mediated by G(s)-alpha protein that stimulate adenylate cyclase, resulting in an elevation of intracellular cAMP.

Subcellular location. Cell membrane.

Tissue specificity. High level of expression in placenta. Expressed throughout the brain at low level. No expression detected in skeletal muscle, lung, heart, liver, pancreas, or kidney.

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

RefSeq proteins (1): NP_543009* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR049579	GPR26/78-like	Family
IPR051880	GPC_Orphan_Receptors	Family

Pfam: PF00001

UniProt features (25 total): topological domain 8, transmembrane region 7, sequence variant 3, sequence conflict 2, chain 1, region of interest 1, compositionally biased region 1, disulfide bond 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96P69-F1	84.35	0.60

Functional residue map

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

Disulfide bonds (1): 79–156

Mutagenesis-validated functional residues (1):

Position	Phenotype
236	no effect on constitutive activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 27 (showing top): GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, chr4p16, HAMAI_APOPTOSIS_VIA_TRAIL_DN, GOBP_ADENYLATE_CYCLASE_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, GOBP_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, LMTK3_TARGET_GENES, NFKBIA_TARGET_GENES, PBXIP1_TARGET_GENES, ZNF512_TARGET_GENES, ZNF512B_TARGET_GENES, ZNF7_TARGET_GENES, MIR4531

GO Biological Process (3): adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (2): G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

494 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR78	LPAR1	P78351	810
GPR78	ATF6	P18850	735
GPR78	ERN1	O75460	686
GPR78	HSPA5	P11021	669
GPR78	DNAJC1	Q96KC8	559
GPR78	DDIT3	P35638	477
GPR78	XBP1	P17861	475
GPR78	CRIPTO	P13385	430
GPR78	EIF2AK3	Q9NZJ5	404
GPR78	HSP90B1	P14625	378
GPR78	GPR61	Q9BZJ8	357
GPR78	RDH16	O75452	353
GPR78	THRSP	Q92748	349
GPR78	FDPS	P14324	349
GPR78	ELAVL1	Q15717	349

IntAct

0 interactions, top by confidence:

BioGRID (1): APP (Reconstituted Complex)

ESM2 similar proteins: A0A6I8PUB9, O00155, O00270, O14842, O14843, O15529, O43603, O46685, O60755, O88626, O88634, O88853, O88854, O88855, P0C5I1, P46092, P46093, P50132, Q149R9, Q15722, Q15743, Q1JQB3, Q3T181, Q3UFD7, Q3ZC80, Q4KLH9, Q6XKD3, Q76JU8, Q76JU9, Q76JV1, Q86VZ1, Q8BUD0, Q8BYC4, Q8HYC3, Q8K3T4, Q8TDS5, Q8TDU9, Q920E0, Q924U0, Q96G91

Diamond homologs: A6NM03, P16395, P21451, P30729, P48302, P51436, Q59E83, Q8BZA7, Q8NDV2, Q8NGQ2, Q93126, Q96P69, Q9H205, Q9N0W7, Q9QXI3, B2RPY5, O62709, P20905, P21917, P24530, P28088, P35463, P56497, Q1JPS6, Q6TAC8, Q6TLJ0, Q6XL69, Q8NH40, A0A6I8PUB9, O77408

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	95
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2922 predictions. Top by Δscore:

Variant	Effect	Δscore
4:8581648:CAGGT:C	donor_loss	1.0000
4:8581649:AGGTA:A	donor_loss	1.0000
4:8582528:CA:C	acceptor_loss	1.0000
4:8582529:A:AG	acceptor_gain	1.0000
4:8582529:A:C	acceptor_loss	1.0000
4:8582529:AGT:A	acceptor_gain	1.0000
4:8582529:AGTGT:A	acceptor_gain	1.0000
4:8582530:G:C	acceptor_loss	1.0000
4:8582530:G:GA	acceptor_gain	1.0000
4:8582530:GT:G	acceptor_gain	1.0000
4:8582530:GTG:G	acceptor_gain	1.0000
4:8582530:GTGT:G	acceptor_gain	1.0000
4:8582530:GTGTG:G	acceptor_gain	1.0000
4:8582585:G:GT	donor_gain	1.0000
4:8582641:CCAG:C	donor_loss	1.0000
4:8582643:AGGTG:A	donor_loss	1.0000
4:8582644:GGTG:G	donor_loss	1.0000
4:8582645:G:GC	donor_loss	1.0000
4:8582646:T:A	donor_loss	1.0000
4:8587052:AGGCT:A	acceptor_gain	1.0000
4:8587053:GGCTG:G	acceptor_gain	1.0000
4:8601495:GGG:G	donor_gain	1.0000
4:8601496:GG:G	donor_gain	1.0000
4:8601496:GGG:G	donor_gain	1.0000
4:8601497:GG:G	donor_gain	1.0000
4:8601497:GGTA:G	donor_loss	1.0000
4:8601498:G:GG	donor_gain	1.0000
4:8601498:G:T	donor_loss	1.0000
4:8601499:T:G	donor_loss	1.0000
4:8603975:GGA:G	acceptor_gain	1.0000

AlphaMissense

2283 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:8587106:A:C	S279R	0.981
4:8587108:C:A	S279R	0.981
4:8587108:C:G	S279R	0.981
4:8587124:A:C	S285R	0.975
4:8587126:C:A	S285R	0.975
4:8587126:C:G	S285R	0.975
4:8581123:T:A	N47K	0.974
4:8581123:T:G	N47K	0.974
4:8582610:T:C	F250L	0.969
4:8582612:C:A	F250L	0.969
4:8582612:C:G	F250L	0.969
4:8582629:C:G	P256R	0.968
4:8581268:A:C	S96R	0.967
4:8581270:C:A	S96R	0.967
4:8581270:C:G	S96R	0.967
4:8582629:C:A	P256Q	0.965
4:8581496:T:C	F172L	0.964
4:8581498:C:A	F172L	0.964
4:8581498:C:G	F172L	0.964
4:8581439:T:C	F153L	0.961
4:8581441:C:A	F153L	0.961
4:8581441:C:G	F153L	0.961
4:8581487:T:C	F169L	0.958
4:8581489:C:A	F169L	0.958
4:8581489:C:G	F169L	0.958
4:8587111:G:C	K280N	0.958
4:8587111:G:T	K280N	0.958
4:8581373:T:A	W131R	0.954
4:8581373:T:C	W131R	0.954
4:8581523:T:C	F181L	0.954

dbSNP variants (sampled 300 via entrez): RS10000720 (4:8582368 C>A,G,T), RS1000297181 (4:8585203 C>T), RS10006769 (4:8584035 C>T), RS1000731675 (4:8580576 A>G), RS1000761743 (4:8580700 G>C), RS1000816513 (4:8589950 A>G,T), RS1000882171 (4:8586636 C>T), RS1001062120 (4:8579134 G>T), RS1001118890 (4:8587652 T>C), RS1001395009 (4:8583727 G>A), RS1001451292 (4:8580344 C>T), RS1001459938 (4:8582810 A>C,G), RS1001502080 (4:8580190 C>T), RS1001765588 (4:8583937 A>T), RS1001837269 (4:8580899 G>A,T)

Disease associations

OMIM: gene MIM:606921 | 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
GCST005754_2	Systemic lupus erythematosus	3.000000e-11
GCST008163_138	Height	8.000000e-06
GCST008600_2	Longevity (age >90th survival percentile)	2.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523908 (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 no pharmacology

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	decreases expression	1
terbufos	decreases methylation	1
MT19c compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Fonofos	decreases methylation	1
Estradiol	decreases expression	1
Parathion	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	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
CHEMBL4883468	Binding	PRESTO-Tango GPCRome screening (GPR78)	Data for DCP probe UCSF924

Cellosaurus cell lines

2 cell lines: 1 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KX72	PathHunter CHO-K1 GPR78 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_XP34	HAP1 GPR78 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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