Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIBF32I)

DOT Name G-protein coupled receptor 4 (GPR4)
Synonyms G-protein coupled receptor 6C.l; GPR6C.l
Gene Name GPR4
Related Disease
Colitis ( )
Prostate cancer ( )
Colorectal carcinoma ( )
Dermatofibrosarcoma protuberans ( )
Head and neck cancer ( )
Head and neck carcinoma ( )
Head-neck squamous cell carcinoma ( )
Lung cancer ( )
Lung carcinoma ( )
Maple syrup urine disease ( )
Myotonic dystrophy ( )
Neoplasm ( )
Prostate carcinoma ( )
46,XY sex reversal 2 ( )
Advanced cancer ( )
Charcot-Marie-Tooth disease type 3 ( )
Epithelial ovarian cancer ( )
Inflammatory bowel disease ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
UniProt ID
GPR4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF00001
Sequence
MGNHTWEGCHVDSRVDHLFPPSLYIFVIGVGLPTNCLALWAAYRQVQQRNELGVYLMNLS
IADLLYICTLPLWVDYFLHHDNWIHGPGSCKLFGFIFYTNIYISIAFLCCISVDRYLAVA
HPLRFARLRRVKTAVAVSSVVWATELGANSAPLFHDELFRDRYNHTFCFEKFPMEGWVAW
MNLYRVFVGFLFPWALMLLSYRGILRAVRGSVSTERQEKAKIKRLALSLIAIVLVCFAPY
HVLLLSRSAIYLGRPWDCGFEERVFSAYHSSLAFTSLNCVADPILYCLVNEGARSDVAKA
LHNLLRFLASDKPQEMANASLTLETPLTSKRNSTAKAMTGSWAATPPSQGDQVQLKMLPP
AQ
Function
Proton-sensing G-protein coupled receptor couples to multiple intracellular signaling pathways, including GNAS/cAMP, GNAQ/phospholipase C (PLC), and GNA12/GNA13/Rho pathways. Acidosis-induced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the GNA12/GNA13/Rho GTPase signaling pathway. In the brain may mediate central respiratory sensitivity to CO(2)H(+).
Reactome Pathway
G alpha (q) signalling events (R-HSA-416476 )
Class A/1 (Rhodopsin-like receptors) (R-HSA-373076 )

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Colitis DISAF7DD Definitive Biomarker [1]
Prostate cancer DISF190Y Definitive Altered Expression [2]
Colorectal carcinoma DIS5PYL0 Strong Altered Expression [3]
Dermatofibrosarcoma protuberans DIS4OCQM Strong Altered Expression [4]
Head and neck cancer DISBPSQZ Strong Biomarker [5]
Head and neck carcinoma DISOU1DS Strong Biomarker [5]
Head-neck squamous cell carcinoma DISF7P24 Strong Biomarker [5]
Lung cancer DISCM4YA Strong Altered Expression [6]
Lung carcinoma DISTR26C Strong Altered Expression [6]
Maple syrup urine disease DIS61XRH Strong Biomarker [7]
Myotonic dystrophy DISNBEMX Strong Biomarker [8]
Neoplasm DISZKGEW Strong Altered Expression [3]
Prostate carcinoma DISMJPLE Disputed Altered Expression [2]
46,XY sex reversal 2 DIS0USUN Limited Biomarker [9]
Advanced cancer DISAT1Z9 Limited Biomarker [7]
Charcot-Marie-Tooth disease type 3 DIS6DQK1 Limited Biomarker [9]
Epithelial ovarian cancer DIS56MH2 Limited Biomarker [10]
Inflammatory bowel disease DISGN23E Limited Altered Expression [9]
Ovarian cancer DISZJHAP Limited Altered Expression [10]
Ovarian neoplasm DISEAFTY Limited Altered Expression [10]
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⏷ Show the Full List of 20 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of G-protein coupled receptor 4 (GPR4). [11]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of G-protein coupled receptor 4 (GPR4). [14]
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5 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of G-protein coupled receptor 4 (GPR4). [12]
Methotrexate DM2TEOL Approved Methotrexate decreases the expression of G-protein coupled receptor 4 (GPR4). [13]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of G-protein coupled receptor 4 (GPR4). [15]
QUERCITRIN DM1DH96 Investigative QUERCITRIN increases the expression of G-protein coupled receptor 4 (GPR4). [16]
Lysophosphatidylcholine DMOGFVH Investigative Lysophosphatidylcholine increases the expression of G-protein coupled receptor 4 (GPR4). [17]
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References

1 Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model.Eur J Pharmacol. 2019 Jun 5;852:218-230. doi: 10.1016/j.ejphar.2019.03.038. Epub 2019 Mar 28.
2 Lgr4 promotes prostate tumorigenesis through the Jmjd2a/AR signaling pathway.Exp Cell Res. 2016 Nov 15;349(1):77-84. doi: 10.1016/j.yexcr.2016.09.023. Epub 2016 Oct 12.
3 Increased proton-sensing receptor GPR4 signalling promotes colorectal cancer progression by activating the hippo pathway.EBioMedicine. 2019 Oct;48:264-276. doi: 10.1016/j.ebiom.2019.09.016. Epub 2019 Sep 14.
4 Expression of proton-sensing G-protein-coupled receptors in selected skin tumors.Exp Dermatol. 2019 Jan;28(1):66-71. doi: 10.1111/exd.13809. Epub 2018 Dec 13.
5 The Proton-Sensing G-Protein Coupled Receptor GPR4 Promotes Angiogenesis in Head and Neck Cancer.PLoS One. 2016 Apr 14;11(4):e0152789. doi: 10.1371/journal.pone.0152789. eCollection 2016.
6 Expression of G protein-coupled receptor 19 in human lung cancer cells is triggered by entry into S-phase and supports G(2)-M cell-cycle progression.Mol Cancer Res. 2012 Oct;10(10):1343-58. doi: 10.1158/1541-7786.MCR-12-0139. Epub 2012 Aug 21.
7 Genome-wide screening identifies novel genes implicated in cellular sensitivity to BRAF(V600E) expression.Oncogene. 2020 Jan;39(4):723-738. doi: 10.1038/s41388-019-1022-0. Epub 2019 Sep 23.
8 Isolation of a novel G protein-coupled receptor (GPR4) localized to chromosome 19q13.3.Genomics. 1995 Nov 1;30(1):84-8. doi: 10.1006/geno.1995.0013.
9 GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis.Biochim Biophys Acta Mol Basis Dis. 2017 Feb;1863(2):569-584. doi: 10.1016/j.bbadis.2016.12.005. Epub 2016 Dec 7.
10 Relations between GPR4 expression, microvascular density (MVD) and clinical pathological characteristics of patients with epithelial ovarian carcinoma (EOC).Curr Pharm Des. 2014;20(11):1904-16. doi: 10.2174/13816128113199990530.
11 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
12 Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
13 Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
14 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
15 Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
16 Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
17 Lysophosphatidylcholine induces apoptosis and inflammatory damage in brain microvascular endothelial cells via GPR4-mediated NLRP3 inflammasome activation. Toxicol In Vitro. 2021 Dec;77:105227. doi: 10.1016/j.tiv.2021.105227. Epub 2021 Jul 20.