GPR135

Summary

GPR135 (G protein-coupled receptor 135, HGNC:19991) is a protein-coding gene on chromosome 14q23.1, encoding G-protein coupled receptor 135 (Q8IZ08). Orphan receptor.

Enables arrestin family protein binding activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Located in endosome and plasma membrane.

Source: NCBI Gene 64582 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 109 total
• Druggable target: yes
• MANE Select transcript: NM_022571

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19991
Approved symbol	GPR135
Name	G protein-coupled receptor 135
Location	14q23.1
Locus type	gene with protein product
Status	Approved
Aliases	HUMNPIIY20, PAFR
Ensembl gene	ENSG00000181619
Ensembl biotype	protein_coding
OMIM	607970
Entrez	64582

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 nonsense_mediated_decay

ENST00000395116, ENST00000481661

RefSeq mRNA: 1 — MANE Select: NM_022571 NM_022571

CCDS: CCDS9738

Canonical transcript exons

ENST00000395116 — 1 exons

Exon	Start	End
ENSE00001520643	59460759	59465380

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 83.91.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2713 / max 38.3422, expressed in 127 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143444	0.2713	127

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	83.91	gold quality
right testis	UBERON:0004534	83.83	gold quality
sperm	CL:0000019	81.60	gold quality
testis	UBERON:0000473	81.57	gold quality
male germ cell	CL:0000015	80.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.78	gold quality
right uterine tube	UBERON:0001302	78.05	gold quality
buccal mucosa cell	CL:0002336	75.25	silver quality
triceps brachii	UBERON:0001509	75.17	gold quality
right coronary artery	UBERON:0001625	75.01	gold quality
ventricular zone	UBERON:0003053	73.31	gold quality
left coronary artery	UBERON:0001626	73.04	gold quality
popliteal artery	UBERON:0002250	72.56	gold quality
tibial artery	UBERON:0007610	72.54	gold quality
stromal cell of endometrium	CL:0002255	72.16	gold quality
gluteal muscle	UBERON:0002000	72.11	gold quality
aorta	UBERON:0000947	72.05	gold quality
hair follicle	UBERON:0002073	71.90	gold quality
ascending aorta	UBERON:0001496	71.84	gold quality
thoracic aorta	UBERON:0001515	71.81	gold quality
coronary artery	UBERON:0001621	71.42	gold quality
right ovary	UBERON:0002118	70.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	70.67	gold quality
lower esophagus	UBERON:0013473	70.65	gold quality
adenohypophysis	UBERON:0002196	70.56	gold quality
left ovary	UBERON:0002119	70.55	gold quality
descending thoracic aorta	UBERON:0002345	70.49	gold quality
pituitary gland	UBERON:0000007	70.26	gold quality
bronchial epithelial cell	CL:0002328	70.09	silver quality
body of uterus	UBERON:0009853	69.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

19 targeting GPR135, 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-6740-5P	100.00	65.64	932
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-4475	97.36	66.95	761
HSA-MIR-4445-5P	97.21	66.16	832
HSA-MIR-1251-5P	95.78	64.10	374

Literature-anchored findings (GeneRIF, showing 2)

• GPR135 hypermethylation is associated with lung cancer. (PMID:28722770)
• Collectively, these data show that GPR61, GPR62 and GPR135 are unable to bind melatonin, but show a reciprocal regulatory interaction with MT2 receptors. (PMID:28827538)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpr135	ENSDARG00000028586
mus_musculus	Gpr135	ENSMUSG00000043398
rattus_norvegicus	Gpr135	ENSRNOG00000004499

Paralogs (3): GPR61 (ENSG00000156097), GPR176 (ENSG00000166073), GPR62 (ENSG00000180929)

Protein

Protein identifiers

G-protein coupled receptor 135 — Q8IZ08 (reviewed: Q8IZ08)

All UniProt accessions (1): Q8IZ08

UniProt curated annotations — full annotation on UniProt →

Function. Orphan receptor. Has spontaneous activity for beta-arrestin recruitment. Shows a reciprocal regulatory interaction with the melatonin receptor MTNR1B most likely through receptor heteromerization.

Subunit / interactions. Interacts with MTNR1B. Interacts with ARRB1 and ARRB2 in a spontaneous and agonist-independent manner; leading to the internalization of GPR135 in the endosomal compartment.

Subcellular location. Cell membrane. Endosome membrane.

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

RefSeq proteins (1): NP_072093* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (23 total): topological domain 8, transmembrane region 7, compositionally biased region 3, region of interest 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZ08-F1	68.52	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 53 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, chr14q23, TGGAAA_NFAT_Q4_01, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, MULLIGHAN_NPM1_MUTATED_SIGNATURE_1_UP, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, GOBP_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, PURBEY_TARGETS_OF_CTBP1_AND_SATB1_UP, GOMF_ARRESTIN_FAMILY_PROTEIN_BINDING, STK33_SKM_UP, STK33_UP, NFE2L2.V2, GOCC_ENDOSOME_MEMBRANE, MIR96_5P

GO Biological Process (2): G protein-coupled receptor signaling pathway (GO:0007186), signal transduction (GO:0007165)

GO Molecular Function (3): G protein-coupled receptor activity (GO:0004930), arrestin family protein binding (GO:1990763), protein binding (GO:0005515)

GO Cellular Component (4): endosome (GO:0005768), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	1
signal transduction	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
protein binding	1
binding	1
endomembrane system	1
cytoplasmic vesicle	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR135	PTAFR	P25105	861
GPR135	GPR62	Q9BZJ7	634
GPR135	RLN3	Q8WXF3	568
GPR135	ARRB1	P49407	559
GPR135	GNAQ	P50148	511
GPR135	CARNS1	A5YM72	478
GPR135	PLA2G7	Q13093	449
GPR135	LPCAT2	Q7L5N7	447
GPR135	GPR141	Q7Z602	439
GPR135	GPR150	Q8NGU9	437
GPR135	GPR162	Q16538	434
GPR135	GPR142	Q7Z601	429
GPR135	CAV1	Q03135	419
GPR135	GPR137	Q96N19	403
GPR135	LPCAT1	Q8NF37	395

IntAct

5 interactions, top by confidence:

A	B	Type	Score
GPR135	SMC2	psi-mi:“MI:0915”(physical association)	0.400
ZDHHC17	GPR135	psi-mi:“MI:0915”(physical association)	0.370
MAGED1	GPR135	psi-mi:“MI:0915”(physical association)	0.000
GPR135	TPD52L1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (7): GPR135 (Two-hybrid), GPR135 (Affinity Capture-RNA), GPR135 (Two-hybrid), GPR135 (Two-hybrid), GPR135 (Affinity Capture-MS), GPR135 (Proximity Label-MS), GPR135 (Affinity Capture-RNA)

ESM2 similar proteins: O02662, O02666, O43603, O70432, O95665, P08588, P13945, P18090, P18825, P18871, P21917, P22086, P25100, P25962, P26255, P30729, P31387, P34971, P35365, P46626, P47899, P50406, P51436, P79148, P97714, Q01337, Q28524, Q28927, Q28998, Q5IS65, Q60474, Q60476, Q60483, Q6TLJ0, Q7TQN7, Q7TQP2, Q80UC6, Q8IZ08, Q91V45, Q924U1

Diamond homologs: A0A287A2K5, O02836, O08786, O35210, O42179, O43193, O57422, O60755, O77408, O77590, O88626, O88853, O97772, P08483, P08911, P11483, P20309, P22270, P25095, P25104, P29089, P29754, P30551, P30552, P30553, P30555, P30556, P30796, P32238, P32239, P34976, P41984, P43240, P46627, P49146, P49219, P49286, P49287, P49288, P49578

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	106
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

51 predictions. Top by Δscore:

Variant	Effect	Δscore
14:59461173:CCTTA:C	acceptor_gain	0.8700
14:59461262:TTAC:T	acceptor_gain	0.8300
14:59461174:CTTA:C	acceptor_gain	0.7700
14:59461175:TTAT:T	acceptor_gain	0.7700
14:59461263:TA:T	acceptor_gain	0.7300
14:59461264:A:T	acceptor_gain	0.7300
14:59461307:TCTG:T	acceptor_gain	0.7000
14:59461260:CCTT:C	acceptor_gain	0.6600
14:59461265:C:G	acceptor_gain	0.6400
14:59462871:T:TG	acceptor_gain	0.6000
14:59461261:CTTA:C	acceptor_gain	0.5900
14:59461266:C:G	acceptor_gain	0.5900
14:59461273:CTT:C	acceptor_gain	0.5600
14:59461175:T:C	acceptor_gain	0.5200
14:59461302:G:GT	acceptor_gain	0.5200
14:59461367:T:TG	acceptor_gain	0.5100
14:59461308:C:A	acceptor_gain	0.4700
14:59462150:CT:C	donor_gain	0.4700
14:59462151:TT:T	donor_gain	0.4700
14:59462152:TT:T	donor_gain	0.4700
14:59462872:C:G	acceptor_gain	0.4600
14:59461301:TG:T	acceptor_gain	0.4000
14:59461272:ACT:A	acceptor_gain	0.3800
14:59465021:C:CT	donor_gain	0.3600
14:59461177:ATAT:A	acceptor_gain	0.3500
14:59461176:TATA:T	acceptor_gain	0.3400
14:59463713:G:A	donor_gain	0.3300
14:59461267:T:G	acceptor_gain	0.3200
14:59461274:T:A	acceptor_gain	0.3200
14:59463897:T:TA	donor_gain	0.3200

AlphaMissense

3124 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:59464361:G:C	P289R	0.997
14:59464624:G:C	S201R	0.997
14:59464624:G:T	S201R	0.997
14:59464626:T:G	S201R	0.997
14:59464361:G:T	P289H	0.996
14:59464864:G:C	N121K	0.996
14:59464864:G:T	N121K	0.996
14:59464873:G:C	S118R	0.996
14:59464873:G:T	S118R	0.996
14:59464875:T:G	S118R	0.996
14:59464076:G:T	P384H	0.995
14:59464194:C:G	G345R	0.995
14:59464194:C:T	G345R	0.995
14:59464527:A:G	W234R	0.995
14:59464527:A:T	W234R	0.995
14:59464810:G:C	N139K	0.995
14:59464810:G:T	N139K	0.995
14:59464058:C:G	R390P	0.993
14:59464076:G:C	P384R	0.993
14:59464601:C:G	R209P	0.993
14:59464610:G:C	S206W	0.993
14:59464802:A:T	I142N	0.993
14:59464869:C:G	G120R	0.993
14:59464602:G:T	R209S	0.992
14:59464613:A:T	I205N	0.991
14:59464790:G:T	S146Y	0.991
14:59464054:A:C	N391K	0.990
14:59464054:A:T	N391K	0.990
14:59464070:A:T	I386N	0.990
14:59464085:G:T	A381D	0.990

dbSNP variants (sampled 300 via entrez): RS1000134954 (14:59453806 C>T), RS1000189315 (14:59452504 T>C), RS1000234658 (14:59456455 G>A,T), RS1000259062 (14:59456239 A>G), RS1000463308 (14:59454138 AC>A), RS1001045259 (14:59466225 G>C,T), RS1001196279 (14:59462460 G>C,T), RS1001740577 (14:59455605 G>A), RS1002117739 (14:59457004 G>T), RS1002146138 (14:59456686 C>A,T), RS1002400435 (14:59463311 C>G), RS1002469250 (14:59457049 T>G), RS1002620597 (14:59452306 C>A), RS1002819188 (14:59463544 T>G), RS1003122924 (14:59458425 G>A)

Disease associations

OMIM: gene MIM:607970 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007208_1	Obsessive-compulsive disorder	9.000000e-07
GCST010703_89	Brain morphology (MOSTest)	1.000000e-76

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3309102 (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

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, increases expression	3
Estradiol	increases expression, affects cotreatment	2
Smoke	decreases expression	2
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases expression	1
testosterone undecanoate	increases expression, affects cotreatment	1
beta-lapachone	increases expression	1
sulforaphane	increases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	affects cotreatment, decreases expression	1
Vorinostat	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Asbestos	affects methylation	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cannabidiol	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Ozone	affects expression, increases abundance	1
Silicon Dioxide	increases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3362658	Binding	Agonist activity against human GPR135 assessed as melanophore absorbance by summary (Abse5) assay	Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120). — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KX30	PathHunter CHO-K1 GPR135 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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