Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCF5O4G)

• DOT Name: Psychosine receptor (GPR65)
• Synonyms: G-protein coupled receptor 65; T-cell death-associated gene 8 protein
• Gene Name: GPR65
• Related Disease:
  Acidosis
  Adult glioblastoma
  Adult lymphoma
  Advanced cancer
  Asthma
  Bone cancer
  Bone osteosarcoma
  Depression
  Dermatofibrosarcoma protuberans
  Glioma
  Heparin-induced thrombocytopenia
  Inflammatory bowel disease
  Lymphoma
  Multiple sclerosis
  Myocardial infarction
  Nervous system inflammation
  Panic disorder
  Parkinson disease
  Pediatric lymphoma
  Ulcerative colitis
  Chronic obstructive pulmonary disease
  Rheumatoid arthritis
  Ankylosing spondylitis
  Autoimmune disease
  Colitis
  Crohn disease
  Inflammation
• UniProt ID: PSYR_HUMAN
• Pfam ID: PF00001
• Sequence:
  MNSTCIEEQHDLDHYLFPIVYIFVIIVSIPANIGSLCVSFLQAKKESELGIYLFSLSLSD
  LLYALTLPLWIDYTWNKDNWTFSPALCKGSAFLMYMNFYSSTAFLTCIAVDRYLAVVYPL
  KFFFLRTRRFALMVSLSIWILETIFNAVMLWEDETVVEYCDAEKSNFTLCYDKYPLEKWQ
  INLNLFRTCTGYAIPLVTILICNRKVYQAVRHNKATENKEKKRIIKLLVSITVTFVLCFT
  PFHVMLLIRCILEHAVNFEDHSNSGKRTYTMYRITVALTSLNCVADPILYCFVTETGRYD
  MWNILKFCTGRCNTSQRQRKRILSVSTKDTMELEVLE
• Function: Receptor for the glycosphingolipid psychosine (PSY) and several related glycosphingolipids. Plays a role in immune response by maintaining lysosome function and supporting phagocytosis-mediated intracellular bacteria clearance. May have a role in activation-induced cell death or differentiation of T-cells.
• Tissue Specificity: Predominantly expressed in thymus, spleen, lymph nodes, small intestine, lung, placenta and peripheral blood leukocytes.
• 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

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acidosis	DISJQTX1	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Asthma	DISW9QNS	Strong	Altered Expression	[4]
Bone cancer	DIS38NA0	Strong	Altered Expression	[5]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Dermatofibrosarcoma protuberans	DIS4OCQM	Strong	Altered Expression	[7]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Heparin-induced thrombocytopenia	DISAKJKZ	Strong	Genetic Variation	[8]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[9]
Lymphoma	DISN6V4S	Strong	Biomarker	[3]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[10]
Myocardial infarction	DIS655KI	Strong	Biomarker	[11]
Nervous system inflammation	DISB3X5A	Strong	Altered Expression	[10]
Panic disorder	DISD3VNY	Strong	Altered Expression	[12]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[13]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[3]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[9]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Genetic Variation	[14]
Rheumatoid arthritis	DISTSB4J	Disputed	Biomarker	[15]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[16]
Autoimmune disease	DISORMTM	Limited	Biomarker	[17]
Colitis	DISAF7DD	Limited	Biomarker	[17]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[18]
Inflammation	DISJUQ5T	Limited	Altered Expression	[19]

4 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Psychosine receptor (GPR65).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Psychosine receptor (GPR65).	[21]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Psychosine receptor (GPR65).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Psychosine receptor (GPR65).	[24]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Psychosine receptor (GPR65).	[23]

References

• [1] Identification of T cell death-associated gene 8 (TDAG8) as a novel acid sensing G-protein-coupled receptor.J Biol Chem. 2005 Mar 11;280(10):9083-7. doi: 10.1074/jbc.M407832200. Epub 2004 Dec 23.
• [2] Overexpression of G-protein-coupled receptors 65 in glioblastoma predicts poor patient prognosis.Clin Neurol Neurosurg. 2018 Jan;164:132-137. doi: 10.1016/j.clineuro.2017.11.017. Epub 2017 Nov 29.
• [3] Acidosis decreases c-Myc oncogene expression in human lymphoma cells: a role for the proton-sensing G protein-coupled receptor TDAG8.Int J Mol Sci. 2013 Oct 11;14(10):20236-55. doi: 10.3390/ijms141020236.
• [4] Identification of novel candidate genes involved in the progression of emphysema by bioinformatic methods.Int J Chron Obstruct Pulmon Dis. 2018 Nov 14;13:3733-3747. doi: 10.2147/COPD.S183100. eCollection 2018.
• [5] TDAG8 involved in initiating inflammatory hyperalgesia and establishing hyperalgesic priming in mice.Sci Rep. 2017 Feb 1;7:41415. doi: 10.1038/srep41415.
• [6] Immunomodulatory T cell death associated gene-8 (TDAG8) receptor in depression-associated behaviors.Physiol Behav. 2019 Oct 1;209:112598. doi: 10.1016/j.physbeh.2019.112598. Epub 2019 Jul 2.
• [7] 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.
• [8] A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record.Thromb Haemost. 2015 Apr;113(4):772-81. doi: 10.1160/TH14-08-0670. Epub 2014 Dec 11.
• [9] The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation.BMC Gastroenterol. 2019 Jan 7;19(1):2. doi: 10.1186/s12876-018-0922-8.
• [10] GPR65 inhibits experimental autoimmune encephalomyelitis through CD4(+) T cell independent mechanisms that include effects on iNKT cells.Immunol Cell Biol. 2018 Feb;96(2):128-136. doi: 10.1111/imcb.1031. Epub 2017 Dec 19.
• [11] The proton-sensing G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) shows cardioprotective effects against myocardial infarction.Sci Rep. 2017 Aug 10;7(1):7812. doi: 10.1038/s41598-017-07573-2.
• [12] Acid-sensing T cell death associated gene-8 receptor expression in panic disorder.Brain Behav Immun. 2018 Jan;67:36-41. doi: 10.1016/j.bbi.2017.07.014. Epub 2017 Jul 20.
• [13] A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci.Nat Genet. 2017 Oct;49(10):1511-1516. doi: 10.1038/ng.3955. Epub 2017 Sep 11.
• [14] The clinical and genetic features of COPD-asthma overlap syndrome.Eur Respir J. 2014 Aug;44(2):341-50. doi: 10.1183/09031936.00216013. Epub 2014 May 29.
• [15] TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis.Sci Rep. 2017 Aug 21;7(1):8870. doi: 10.1038/s41598-017-09200-6.
• [16] Genetic polymorphisms of G protein-coupled receptor 65 gene are associated with ankylosing spondylitis in a Chinese Han population: A case-control study.Hum Immunol. 2019 Feb;80(2):146-150. doi: 10.1016/j.humimm.2018.12.001. Epub 2018 Dec 4.
• [17] Lack of the pH-sensing Receptor TDAG8 [GPR65] in Macrophages Plays a Detrimental Role in Murine Models of Inflammatory Bowel Disease.J Crohns Colitis. 2019 Feb 1;13(2):245-258. doi: 10.1093/ecco-jcc/jjy152.
• [18] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [19] Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis.Nat Commun. 2017 Nov 15;8(1):1510. doi: 10.1038/s41467-017-01771-2.
• [20] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [21] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [22] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [23] 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.
• [24] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.