GPR68

Summary

GPR68 (G protein-coupled receptor 68, HGNC:4519) is a protein-coding gene on chromosome 14q32.11, encoding G-protein coupled receptor 68 (Q15743). Proton-sensing G-protein coupled receptor activated by extracellular pH, which is required to monitor pH changes and generate adaptive reactions.

The protein encoded by this gene is a G protein-coupled receptor for sphingosylphosphorylcholine. The encoded protein is a proton-sensing receptor, inactive at pH 7.8 but active at pH 6.8. Mutations in this gene are a cause of amelogenesis imperfecta.

Source: NCBI Gene 8111 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amelogenesis imperfecta, hypomaturation type, IIa6 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 82 total — 4 pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes
• MANE Select transcript: NM_001177676

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4519
Approved symbol	GPR68
Name	G protein-coupled receptor 68
Location	14q32.11
Locus type	gene with protein product
Status	Approved
Aliases	OGR1
Ensembl gene	ENSG00000119714
Ensembl biotype	protein_coding
OMIM	601404
Entrez	8111

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000529102, ENST00000529300, ENST00000531499, ENST00000535815, ENST00000650645, ENST00000904053, ENST00000904054, ENST00000904055, ENST00000904056

RefSeq mRNA: 3 — MANE Select: NM_001177676 NM_001177676, NM_001348437, NM_003485

CCDS: CCDS9894

Canonical transcript exons

ENST00000650645 — 2 exons

Exon	Start	End
ENSE00002169983	91232532	91235179
ENSE00003850785	91244297	91244704

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 89.64.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2183 / max 74.3501, expressed in 640 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144498	1.5212	536
144495	0.3516	106
144496	0.1573	58
144497	0.1316	59
144499	0.0565	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	89.64	gold quality
granulocyte	CL:0000094	86.72	gold quality
gingival epithelium	UBERON:0001949	86.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.42	gold quality
gingiva	UBERON:0001828	86.11	gold quality
cardia of stomach	UBERON:0001162	85.29	silver quality
pylorus	UBERON:0001166	83.88	gold quality
buccal mucosa cell	CL:0002336	82.12	gold quality
saphenous vein	UBERON:0007318	79.47	silver quality
pituitary gland	UBERON:0000007	79.44	gold quality
penis	UBERON:0000989	78.85	gold quality
vena cava	UBERON:0004087	78.45	gold quality
amniotic fluid	UBERON:0000173	78.23	gold quality
pharyngeal mucosa	UBERON:0000355	78.00	silver quality
pericardium	UBERON:0002407	77.77	silver quality
superior surface of tongue	UBERON:0007371	77.64	silver quality
adenohypophysis	UBERON:0002196	77.47	gold quality
nipple	UBERON:0002030	76.58	silver quality
tongue	UBERON:0001723	76.06	silver quality
blood	UBERON:0000178	75.99	gold quality
esophagus mucosa	UBERON:0002469	75.56	gold quality
lymph node	UBERON:0000029	75.54	gold quality
endothelial cell	CL:0000115	75.47	silver quality
mucosa of transverse colon	UBERON:0004991	75.18	gold quality
stromal cell of endometrium	CL:0002255	75.02	gold quality
esophagus squamous epithelium	UBERON:0006920	74.83	silver quality
lateral nuclear group of thalamus	UBERON:0002736	74.51	gold quality
trachea	UBERON:0003126	74.51	silver quality
inferior vagus X ganglion	UBERON:0005363	74.37	gold quality
fundus of stomach	UBERON:0001160	74.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting GPR68, 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-5193	100.00	67.26	1744
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-885-5P	99.59	68.59	879
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4504	99.10	69.14	1328

Literature-anchored findings (GeneRIF, showing 35)

• ovarian cancer G-protein-coupled receptor 1 (OGR1), previously described as a receptor for sphingosylphosphorylcholine, acts as a proton-sensing receptor stimulating inositol phosphate formation (PMID:12955148)
• OGR1 was found to evoke strong pH-dependent responses as measured by inositol phosphate accumulation. (PMID:15665078)
• cAMP accumulation may occur through OGR1-mediated stimulation of the phospholipase C/cyclooxygenase/PGI(2) pathway (PMID:16087674)
• OGR1 is a novel metastasis suppressor gene for prostate cancer. OGR1’s constitutive activity via G alpha(i) contributes to its inhibitory effect on cell migration in vitro. (PMID:17728215)
• OGR1/G(q/11)/phospholipase C/protein kinase C pathway regulates osteoblastic COX-2 induction and subsequent PGE(2) production in response to acidic circumstances (PMID:18302504)
• acidic pH-induced vascular actions of aortic smooth muscle cells can be dissected to OGR1-dependent and -independent pathways: COX-2 expression, PGI(2) production, and MKP-1 expression are mediated by OGR1, but PAI-1 expression is not. (PMID:20622109)
• It indicated that OGR1 may be a tumor suppressor gene for ovarian cancer. (PMID:21740742)
• extracellular acidification induces CTGF production through the OGR1/G(q/11) protein and inositol-1,4,5-trisphosphate-induced Ca(2+) mobilization in human airway smooth muscle cells. (PMID:21907704)
• OGR1 activation increased intracellular calcium in transfected HEK293 cells. (PMID:22508039)
• The involvement of ovarian cancer G-protein-coupled receptor 1 in acidic extracellular environment may be an underlying mechanism responsible for bone pain in osteoporosis or bone metastasis without clinically proved fractures. (PMID:22835475)
• the expression of OGR1 in myeloid-derived cells, especially in double positive cells, was required for prostate tumor cell-induced immunosuppression. (PMID:23222714)
• Provide evidence for the roles of OGR1 and ASIC1a in the regulation of intestinal passive Mg(2+) absorption. (PMID:24375028)
• The deconstruction of OGR1-dependent signaling may aid our understanding of mucosal inflammation mechanisms (PMID:26206859)
• Proton-sensing GPCR-YAP Signalling Promotes Cancer-associated Fibroblast Activation of Mesenchymal Stem Cells (PMID:27019624)
• coexpression of OGR1- and G2A-enhanced proton sensitivity and proton-induced calcium signals. This alteration is attributed to oligomerization of OGR1 and G2A. The oligomeric potential locates receptors at a specific site, which leads to enhanced (PMID:27049592)
• Blocking of GPR68 or NF-small ka, CyrillicB activity severely attenuated acidification induced IL-8 production. (PMID:27166427)
• data identify a role for GPR68 as a proton sensor that is required for proper enamel formation (PMID:27693231)
• These results suggest that zOGR1, but not GPR4, is also a metal-sensing G-protein-coupled receptor in addition to a proton-sensing G-protein-coupled receptor, although not all metals that activate hOGR1 activated zOGR1. (PMID:28270026)
• Our results suggest that OGR1-dependent increases in TRPC4 expression may favour formation of highly Ca(2+) -permeable TRPC4-containing channels that promote transformed granule cell migration. Increased motility of cancer cells is a prerequisite for cancer invasion and metastasis, and our findings may point towards a key role for TRPC4 in progression of certain types of medullablastoma. (PMID:28627017)
• different benzodiazepines exhibit a range of biases for OGR1, with sulazepam selectively activating the canonical Gs of the G protein signaling pathway, in heterologous expression systems, as well as in several primary cell types. (PMID:29042451)
• High GPR68 expression is associated with pancreatic ductal adenocarcinoma. (PMID:29092903)
• GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology (PMID:29677517)
• OGR1 expression was correlated with increased expression levels of pro-fibrotic genes and collagen deposition. (PMID:30165600)
• Ovarian cancer G protein coupled receptor 1 (OGR1) (aka GPR68) acts as coincidence detector of membrane stretch and its physiological ligand, extracellular H(+). OGR1 only responds to extracellular acidification under conditions of membrane stretch and vice versa. (PMID:30471999)
• A missense mutation of Leu74Pro of OGR1 found in familial amelogenesis imperfecta actually causes the loss of the pH-sensing mechanism. (PMID:32279993)
• CRISPR-addressable yeast strains with applications in human G protein-coupled receptor profiling and synthetic biology. (PMID:32358068)
• Expression profiles of proton-sensing G-protein coupled receptors in common skin tumors. (PMID:32948783)
• GPR68 Is a Neuroprotective Proton Receptor in Brain Ischemia. (PMID:33059544)
• The evolution and mechanism of GPCR proton sensing. (PMID:33478938)
• pH-Sensing G Protein-Coupled Receptor OGR1 (GPR68) Expression and Activation Increases in Intestinal Inflammation and Fibrosis. (PMID:35163345)
• GPR-68 in human lacrimal gland. Detection and possible role in the pathogenesis of dry eye disease. (PMID:35623913)
• Expression of GPR-68 in Human Corneal and Conjunctival Epithelium. Possible indicator and mediator of attrition associated inflammation at the ocular surface. (PMID:36503812)
• pH-sensing G protein-coupled orphan receptor GPR68 is expressed in human cartilage and correlates with degradation of extracellular matrix during OA progression. (PMID:38077417)
• Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BKCa channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells. (PMID:38627262)
• A novel mutation in GPR68 causes hypomaturation amelogenesis imperfecta. (PMID:38761453)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	GPR68	ENSDARG00000053711
mus_musculus	Gpr68	ENSMUSG00000047415
rattus_norvegicus	Gpr68	ENSRNOG00000046309

Paralogs (1): LPAR5 (ENSG00000184574)

Protein

Protein identifiers

G-protein coupled receptor 68 — Q15743 (reviewed: Q15743)

Alternative names: G-protein coupled receptor 12A, Ovarian cancer G-protein coupled receptor 1

All UniProt accessions (2): E9PNU7, Q15743

UniProt curated annotations — full annotation on UniProt →

Function. Proton-sensing G-protein coupled receptor activated by extracellular pH, which is required to monitor pH changes and generate adaptive reactions. The receptor is almost silent at pH 7.8 but fully activated at pH 6.8. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as phospholipase C. GPR68 is mainly coupled to G(q) G proteins and mediates production of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Acts as a key mechanosensor of fluid shear stress and membrane stretch. Expressed in endothelial cells of small-diameter resistance arteries, where it mediates flow-induced dilation in response to shear stress. May represents an osteoblastic pH sensor regulating cell-mediated responses to acidosis in bone. Acts as a regulator of calcium-sensing receptor CASR in a seesaw manner: GPR68-mediated signaling inhibits CASR signaling in response to protons, while CASR inhibits GPR68 in presence of extracellular calcium.

Subcellular location. Cell membrane.

Tissue specificity. Found at low level in a wide range of tissues, but significantly expressed in lung, kidney, bone and nervous system.

Disease relevance. Amelogenesis imperfecta, hypomaturation type, 2A6 (AI2A6) [MIM:617217] A defect of enamel formation. The disorder involves both primary and secondary dentitions. The teeth have a shiny agar jelly appearance and the enamel is softer than normal. Brown pigment is present in middle layers of enamel. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by a network of residues that connects an extracellular-facing cavity to Glu-149, a conserved charged residue buried in the transmembrane core of the receptor. Protonation likely drives conformational changes in extracellular loop 2 (ECL2), which stabilizes movement of transmembrane 3 (TM3) and a series of rearrangements that connect the extracellular-facing cavity to Glu-149, a residue only conserved in proton-sensing G-protein coupled receptors. Activated in an allosteric manner by divalent metal ions at the extracellular surface following the order: Cd(2+) > Co(2+) > Ni(2+) > Zn(2+) > Fe(2+) > Ca(2+) > Mg(2+). Activated by the benzodiazepine drug lorazepam, a non-selective GPR68 positive allosteric modulator. Activated by ogerin (ZINC67740571), a selective GPR68 positive allosteric modulator. Activated by small molecule MS48107, a selective positive allosteric modulator. Inhibited by small molecule ogremorphin, inducing ferroptosis in cancer cells.

Domain organisation. A multitude of proton-sensing residues, which include extracellular histidine residues (His-17, His-20, His-84, His-169 and His-269) or triad of buried acidic residues (Asp-67, Glu-149 and Asp-282), contribute to activation of the G-protein coupled receptor activity and pH sensitivity.

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

RefSeq proteins (3): NP_001171147, NP_001335366, NP_003476 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR005389	OGR1_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (75 total): mutagenesis site 26, helix 9, topological domain 8, transmembrane region 7, site 6, sequence variant 4, strand 4, region of interest 2, glycosylation site 2, disulfide bond 2, turn 2, chain 1, compositionally biased region 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8Z68	ELECTRON MICROSCOPY	2.64
9BHM	ELECTRON MICROSCOPY	2.9
9BI6	ELECTRON MICROSCOPY	2.9
8Z3O	ELECTRON MICROSCOPY	3.3
8Z5H	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15743-F1	81.21	0.51

Antibody-complex structures (SAbDab): 3 — 8Z68, 9BHM, 9BI6

Functional residue map

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

Catalytic / active sites (6): 17 (proton sensing); 20 (proton sensing); 84 (proton sensing); 149 (required for activation); 169 (proton sensing); 269 (proton sensing)

Disulfide bonds (2): 13–258, 94–172

Glycosylation sites (2): 3, 8

Mutagenesis-validated functional residues (26):

Position	Phenotype
13	decreased proton-induced g-protein coupled receptor signaling.
17	no effect on ph-sensing activity.
17	decreased but not abolished proton-induced g-protein coupled receptor signaling. failed to stimulate ip formation at ph
20	decreased but not abolished proton-induced g-protein coupled receptor signaling. abolished response to shear stress.
20	failed to stimulate ip formation at ph 6.8, activity is restored at more acid ph.
67	impaired ability to sense protons.
84	decreased but not abolished proton-induced g-protein coupled receptor signaling. failed to stimulate ip formation at ph
85	decreased proton-induced g-protein coupled receptor signaling.
89	no effect on ph-sensing activity.
102	abolished proton-induced g-protein coupled receptor signaling.
118	increased proton-induced g-protein coupled receptor signaling.
127	abolished proton-induced g-protein coupled receptor signaling.
149	mimics the protonation state; more easily activated by protons.
159	no effect on ph-sensing activity.
165	decreased proton-induced g-protein coupled receptor signaling.
169	decreased but not abolished proton-induced g-protein coupled receptor signaling. failed to stimulate ip formation at ph
174	abolished proton-induced g-protein coupled receptor signaling.
175	no effect on ph-sensing activity.
240	increased proton-induced g-protein coupled receptor signaling.
241	increased proton-induced g-protein coupled receptor signaling.
245	decreased but not abolished proton-induced g-protein coupled receptor signaling. severe loss ph-sensing activity.
258	decreased proton-induced g-protein coupled receptor signaling.
269	abolished proton-induced g-protein coupled receptor signaling.
269	decreased but not abolished proton-induced g-protein coupled receptor signaling. failed to stimulate ip formation at ph
282	decreased proton-induced g-protein coupled receptor signaling.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 253 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MYELOID_CELL_DEVELOPMENT, MODULE_255, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, HOFMANN_CELL_LYMPHOMA_UP, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, MODULE_317, GOBP_REGULATION_OF_HORMONE_LEVELS

GO Biological Process (15): inflammatory response (GO:0006954), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), insulin secretion (GO:0030073), monocyte differentiation (GO:0030224), response to fluid shear stress (GO:0034405), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), osteoclast development (GO:0036035), negative regulation of monocyte differentiation (GO:0045656), cellular response to pH (GO:0071467), cellular response to acidic pH (GO:0071468), positive regulation of osteoclast development (GO:2001206), signal transduction (GO:0007165), positive regulation of insulin secretion (GO:0032024)

GO Molecular Function (1): G protein-coupled receptor activity (GO:0004930)

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

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR ligand binding	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
defense response	1
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
phospholipase C activator activity	1
protein secretion	1
peptide hormone secretion	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
response to stress	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
osteoclast differentiation	1
myeloid cell development	1
bone cell development	1
negative regulation of myeloid leukocyte differentiation	1
monocyte differentiation	1
regulation of monocyte differentiation	1
response to pH	1
cellular response to abiotic stimulus	1
response to acidic pH	1
cellular response to pH	1
osteoclast development	1
positive regulation of osteoclast differentiation	1
regulation of osteoclast development	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
transmembrane signaling receptor activity	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

914 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR68	MAP3K4	Q9Y6R4	761
GPR68	ODAPH	Q17RF5	683
GPR68	SACK1H	Q6ZRV2	585
GPR68	SLC24A4	Q8NFF2	580
GPR68	GPR162	Q16538	575
GPR68	GNAQ	P50148	570
GPR68	LPAR1	P78351	568
GPR68	GPR153	Q6NV75	558
GPR68	GPR26	Q8NDV2	557
GPR68	GPR132	Q9UNW8	544
GPR68	LPAR2	Q9HBW0	536
GPR68	ADGRA1	Q86SQ6	530
GPR68	AMTN	Q6UX39	528
GPR68	WDR72	Q3MJ13	523
GPR68	DLX3	O60479	520

IntAct

8 interactions, top by confidence:

A	B	Type	Score
RAMP1	GPR68	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	GPR68	psi-mi:“MI:0915”(physical association)	0.400
GPR68	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
GPR68	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
ECE1	GPR68	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (1): STX7 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A4W3GG95, A7YY44, B0F9W3, B0UXR0, B2GV46, B3G515, B5X337, E7FEL0, O00398, O46685, O70526, P21556, P25023, P25105, P25116, P26824, P30411, P30558, P32299, P43657, P46002, P46093, P49019, P50132, P56488, Q00991, Q15743, Q1JQB3, Q28642, Q3UFD7, Q4G072, Q4KLH9, Q61038, Q62035, Q80Z39, Q8BFQ3, Q8BFU7, Q8BLG2, Q8BMC0, Q8BUD0

Diamond homologs: A0A4W3GG95, A0A6I8PUB9, A6QLE7, D4A7K7, E7FEL0, E9QJ73, O00254, O08675, O46685, P0C0W8, P0C5J4, P32246, P32249, P32250, P34996, P35366, P35383, P41231, P41232, P46093, P47900, P48042, P49650, P49651, P49652, P50132, P56482, P58826, P59902, P79928, P97266, Q149R9, Q15743, Q1JQB3, Q2Y2P0, Q3U6B2, Q3ZC80, Q4G072, Q4KLH9, Q5E9H8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	57
Likely benign	11
Benign	7

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1326287	NM_001177676.2(GPR68):c.78_83delinsC (p.Val27fs)	Pathogenic
268084	NM_001177676.2(GPR68):c.386_835del (p.Phe129_Asn278del)	Pathogenic
268085	NM_001177676.2(GPR68):c.667_668del (p.Lys223fs)	Pathogenic
268086	NM_001177676.2(GPR68):c.221T>C (p.Leu74Pro)	Pathogenic

SpliceAI

768 predictions. Top by Δscore:

Variant	Effect	Δscore
14:91237496:C:CT	acceptor_gain	1.0000
14:91237498:T:C	acceptor_gain	1.0000
14:91237498:T:TC	acceptor_gain	1.0000
14:91237500:G:C	acceptor_gain	1.0000
14:91237500:G:GC	acceptor_gain	1.0000
14:91237503:G:C	acceptor_gain	1.0000
14:91237503:G:GC	acceptor_gain	1.0000
14:91253710:CCTA:C	donor_loss	1.0000
14:91253712:TA:T	donor_loss	1.0000
14:91253713:A:AT	donor_loss	1.0000
14:91253714:C:CT	donor_loss	1.0000
14:91235178:CC:C	acceptor_gain	0.9900
14:91235179:CC:C	acceptor_gain	0.9900
14:91253713:A:AC	donor_gain	0.9900
14:91253714:C:CC	donor_gain	0.9900
14:91253714:CCTG:C	donor_gain	0.9900
14:91235178:CCCT:C	acceptor_loss	0.9800
14:91235181:T:C	acceptor_loss	0.9800
14:91237497:G:C	acceptor_gain	0.9800
14:91238606:A:AC	donor_gain	0.9800
14:91238607:C:CC	donor_gain	0.9800
14:91238715:C:CT	acceptor_gain	0.9800
14:91238715:C:T	acceptor_gain	0.9800
14:91235175:AGACC:A	acceptor_gain	0.9700
14:91235176:GACC:G	acceptor_gain	0.9700
14:91235180:C:CC	acceptor_gain	0.9700
14:91237497:G:T	acceptor_gain	0.9600
14:91237509:C:CT	acceptor_gain	0.9600
14:91237514:A:C	acceptor_gain	0.9600
14:91235180:C:T	acceptor_gain	0.9300

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000039073 (14:91261805 C>G), RS1000128738 (14:91235167 G>A,C,T), RS1000154013 (14:91257249 A>G), RS1000213020 (14:91252194 G>A), RS1000283380 (14:91262963 C>G,T), RS1000306909 (14:91251302 T>C), RS1000338265 (14:91246595 T>C), RS1000341366 (14:91246337 C>T), RS1000412953 (14:91252415 A>G), RS1000575650 (14:91256849 A>G), RS1000619390 (14:91264290 C>G,T), RS1000632430 (14:91264806 C>G), RS1000646710 (14:91252500 G>A), RS1000715903 (14:91259109 C>G), RS1000726821 (14:91264627 C>T)

Disease associations

OMIM: gene MIM:601404 | disease phenotypes: MIM:104500, MIM:617217

GenCC curated gene-disease

Disease	Classification	Inheritance
amelogenesis imperfecta, hypomaturation type, IIa6	Strong	Autosomal recessive
amelogenesis imperfecta type 2	Supportive	Autosomal recessive

Mondo (3): amelogenesis imperfecta (MONDO:0019507), amelogenesis imperfecta, hypomaturation type, IIa6 (MONDO:0014971), amelogenesis imperfecta type 2 (MONDO:0015048)

Orphanet (1): Amelogenesis imperfecta (Orphanet:88661)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000705	Amelogenesis imperfecta
HP:0006285	Enamel hypomineralization
HP:0009102	Anterior open-bite malocclusion

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003518_92	Daytime sleep phenotypes	8.000000e-06
GCST005956_47	Waist-to-hip ratio adjusted for BMI	7.000000e-07
GCST005962_28	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	7.000000e-07
GCST010916_24	Proportion of activated microglia (inferior temporal cortex)	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000567	Amelogenesis Imperfecta	C07.650.800.295.250; C07.793.700.295.250; C16.131.850.800.295.250
C536606	Amelogenesis Imperfecta hypomaturation type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3713916 (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 (5 total), top 5:

Ligand	Action	Affinity	Parameter
OSTN (115-133)	Agonist	6.42	pEC50
CARTPT (76-96)	Agonist	5.98	pEC50
Pomc (141-162)	Agonist	5.89	pEC50
MS48107	Positive	5.85	pKB
ogerin	Positive	4.97	pKB

ChEMBL bioactivities

14 potent at pChembl≥5 of 14 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	EC50	57.54	nM	CHEMBL5665392
7.20	EC50	63.1	nM	CHEMBL5665409
7.04	EC50	91.2	nM	CHEMBL5665414
7.02	EC50	95.5	nM	CHEMBL5665417
6.97	EC50	107.2	nM	CHEMBL5665386
6.96	EC50	109.7	nM	CHEMBL5665399
6.94	EC50	114.8	nM	CHEMBL5665399
6.85	EC50	141.2	nM	ZINC32547799
6.83	EC50	147.9	nM	Ogerin
6.83	EC50	148	nM	Ogerin
6.80	EC50	158.5	nM	CHEMBL5665364
6.80	EC50	158.5	nM	ZINC32547799
6.73	EC50	186.2	nM	CHEMBL5665404

PubChem BioAssay actives

12 with measured affinity, of 337 total; 10 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[3-[4-amino-6-(4-methylanilino)-1,3,5-triazin-2-yl]phenyl]ethanone	2161926: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as cAMP production in presence of H+ proton by Split-luciferase based luminescence counter analysis (Rvb = 6.53 to 6.72 No_unit)	ec50	0.0575	uM
6-(2-aminophenyl)-2-N-benzyl-1,3,5-triazine-2,4-diamine	2161926: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as cAMP production in presence of H+ proton by Split-luciferase based luminescence counter analysis (Rvb = 6.53 to 6.72 No_unit)	ec50	0.0631	uM
2-N-benzyl-6-(3,4-difluorophenyl)-1,3,5-triazine-2,4-diamine	2161926: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as cAMP production in presence of H+ proton by Split-luciferase based luminescence counter analysis (Rvb = 6.53 to 6.72 No_unit)	ec50	0.0912	uM
2-N-benzyl-6-(8-methylquinolin-5-yl)-1,3,5-triazine-2,4-diamine	2161926: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as cAMP production in presence of H+ proton by Split-luciferase based luminescence counter analysis (Rvb = 6.53 to 6.72 No_unit)	ec50	0.0955	uM
(4R)-3-(furan-2-yl)-4-(3-nitrophenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one	2161926: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as cAMP production in presence of H+ proton by Split-luciferase based luminescence counter analysis (Rvb = 6.53 to 6.72 No_unit)	ec50	0.1071	uM
2-N-benzyl-6-(3,5-difluorophenyl)-1,3,5-triazine-2,4-diamine	2161926: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as cAMP production in presence of H+ proton by Split-luciferase based luminescence counter analysis (Rvb = 6.53 to 6.72 No_unit)	ec50	0.1096	uM
[3-[4-amino-6-(benzylamino)-1,3,5-triazin-2-yl]phenyl]methanol	2161919: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as proton-mediated calcium release at 10 uM incubated for 10 mins by Fluo-4 Direct calcium dye based FLIPR assay (Rvb = 6.78 +/- 0.02 No_unit)	ec50	0.1412	uM
[2-[4-amino-6-(benzylamino)-1,3,5-triazin-2-yl]phenyl]methanol	2161919: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as proton-mediated calcium release at 10 uM incubated for 10 mins by Fluo-4 Direct calcium dye based FLIPR assay (Rvb = 6.78 +/- 0.02 No_unit)	ec50	0.1479	uM
(4R)-3-(furan-2-yl)-4-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one	2161926: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as cAMP production in presence of H+ proton by Split-luciferase based luminescence counter analysis (Rvb = 6.53 to 6.72 No_unit)	ec50	0.1585	uM
(4R)-4-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrrolo[3,4-d]pyrazol-6-one	2161926: Positive allosteric modulator activity at GPR68 expressed in human HEK293T cells assessed as cAMP production in presence of H+ proton by Split-luciferase based luminescence counter analysis (Rvb = 6.53 to 6.72 No_unit)	ec50	0.1862	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Benzo(a)pyrene	decreases methylation, affects reaction, increases expression, affects methylation	2
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
boron nitride	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
AICA ribonucleotide	decreases reaction, increases expression, increases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
SC 514	increases reaction, decreases reaction, increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Cisplatin	increases expression	1
Dexamethasone	decreases expression	1
Diuron	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Nickel	increases expression	1
Oxygen	decreases reaction, increases expression, increases reaction, affects binding	1
Polychlorinated Biphenyls	affects expression	1
Silicon Dioxide	decreases expression	1
Smoke	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases methylation	1
beta-Naphthoflavone	increases expression	1

ChEMBL screening assays

21 unique, capped per target: 12 functional, 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3813384	Binding	Antagonist activity at N-terminal HA-tagged OGR1 (unknown origin) expressed in HEK293 cells assessed as inhibition of pH dependent nuclear factor of activated T-cell activity at >1 uM at pH 7.2 incubated for 6 hrs by dual luciferase reporte	Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction. — ACS Med Chem Lett
CHEMBL4178749	Functional	Inhibition of OGR1 (unknown origin) expressed in human HeLa cells assessed as reduction in cAMP accumulation	Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_H444	CHO-K1/GPR68/Galpha15	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01746121	Not specified	TERMINATED	Amelogenesis Imperfecta
NCT02994862	Not specified	UNKNOWN	E. Max Laminate Veneers With and Without Using Galla Chinnesis as Natural Cross Linking and Remineralizing Agent
NCT03810859	Not specified	UNKNOWN	Non-syndromic Inherited Anomalies of Mineralized Tooth Tissues: a Whole Exome Study to Identify New Pathogenic Variants
NCT04704089	Not specified	RECRUITING	Colorimetric, Ultra-structural and Elemental Comparison of Dental Enamel Defects
NCT04897724	Not specified	UNKNOWN	Clinical Performance of Composites in Patients With Amelogenesis Imperfecta
NCT04927962	Not specified	COMPLETED	Psycho-social Impact of Amelogenesis and Dentinogenesis Imperfecta
NCT05343247	Not specified	COMPLETED	Dental Age Estimation by Different Methods in Patients With Amelogenesis Imperfecta
NCT07250906	Not specified	RECRUITING	Oral Health Related Quality of Life of Children With Amelogenesis Imperfecta