Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRA1LOC)

• DOT Name: Regulator of G-protein signaling 9 (RGS9)
• Synonyms: RGS9
• Gene Name: RGS9
• Related Disease:
  Bradyopsia
  Analgesia
  Dystonia
  Graves disease
  Heroin dependence
  Neoplasm
  Neuralgia
  Parkinson disease
  Parkinsonian disorder
  Schizophrenia
  Tardive dyskinesia
  Leber congenital amaurosis
  Psychotic disorder
• UniProt ID: RGS9_HUMAN
• Pfam ID: PF00610 ; PF00631 ; PF00615 ; PF18148
• Sequence:
  MTIRHQGQQYRPRMAFLQKIEALVKDMQNPETGVRMQNQRVLVTSVPHAMTGSDVLQWIV
  QRLWISSLEAQNLGNFIVRYGYIYPLQDPKNLILKPDGSLYRFQTPYFWPTQQWPAEDTD
  YAIYLAKRNIKKKGILEEYEKENYNFLNQKMNYKWDFVIMQAKEQYRAGKERNKADRYAL
  DCQEKAYWLVHRCPPGMDNVLDYGLDRVTNPNEVKVNQKQTVVAVKKEIMYYQQALMRST
  VKSSVSLGGIVKYSEQFSSNDAIMSGCLPSNPWITDDTQFWDLNAKLVEIPTKMRVERWA
  FNFSELIRDPKGRQSFQYFLKKEFSGENLGFWEACEDLKYGDQSKVKEKAEEIYKLFLAP
  GARRWINIDGKTMDITVKGLKHPHRYVLDAAQTHIYMLMKKDSYARYLKSPIYKDMLAKA
  IEPQETTKKSSTLPFMRRHLRSSPSPVILRQLEEEAKAREAANTVDITQPGQHMAPSPHL
  TVYTGTCMPPSPSSPFSSSCRSPRKPFASPSRFIRRPSTTICPSPIRVALESSSGLEQKG
  ECSGSMAPRGPSVTESSEASLDTSWPRSRPRAPPKARMALSFSRFLRRGCLASPVFARLS
  PKCPAVSHGRVQPLGDVGQQLPRLKSKRVANFFQIKMDVPTGSGTCLMDSEDAGTGESGD
  RATEKEVICPWESL
• Function: Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds to GNAT1. Involved in phototransduction; key element in the recovery phase of visual transduction.
• Tissue Specificity: Highly expressed in the caudate and putamen, lower levels found in the hypothalamus and nucleus accumbens and very low levels in cerebellum. Not expressed in globus pallidus or cingulate cortex. Isoform 2 is expressed predominantly in pineal gland and retina. Isoform 3 is expressed in retina (abundant in photoreceptors).
• KEGG Pathway:
  Phototransduction (hsa04744)
  Cocaine addiction (hsa05030)
• Reactome Pathway:
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bradyopsia	DIST8K6C	Definitive	Autosomal recessive	[1]
Analgesia	DISK3TVI	Strong	Biomarker	[2]
Dystonia	DISJLFGW	Strong	Biomarker	[3]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[4]
Heroin dependence	DISQ1H57	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Neuralgia	DISWO58J	Strong	Altered Expression	[2]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[7]
Parkinsonian disorder	DISHGY45	Strong	Therapeutic	[8]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
Tardive dyskinesia	DISKA5RC	Strong	Genetic Variation	[9]
Leber congenital amaurosis	DISMGH8F	Limited	CausalMutation	[10]
Psychotic disorder	DIS4UQOT	Limited	Altered Expression	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Regulator of G-protein signaling 9 (RGS9).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Regulator of G-protein signaling 9 (RGS9).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Regulator of G-protein signaling 9 (RGS9).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Regulator of G-protein signaling 9 (RGS9).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Regulator of G-protein signaling 9 (RGS9).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Regulator of G-protein signaling 9 (RGS9).	[19]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Regulator of G-protein signaling 9 (RGS9).	[20]
Cordycepin	DM72Y01	Investigative	Cordycepin decreases the expression of Regulator of G-protein signaling 9 (RGS9).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Regulator of G-protein signaling 9 (RGS9).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Regulator of G-protein signaling 9 (RGS9).	[18]

References

• [1] Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation. Nature. 2004 Jan 1;427(6969):75-8. doi: 10.1038/nature02170.
• [2] RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States.Neuropsychopharmacology. 2017 Jun;42(7):1548-1556. doi: 10.1038/npp.2017.4. Epub 2017 Jan 11.
• [3] RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models.EMBO Mol Med. 2019 Jan;11(1):e9283. doi: 10.15252/emmm.201809283.
• [4] Thyrotropin receptor antibodies and a genetic hint in antithyroid drug-induced adverse drug reactions.Expert Opin Drug Saf. 2018 Aug;17(8):775-784. doi: 10.1080/14740338.2018.1502747. Epub 2018 Aug 1.
• [5] Evidence for the contribution of genetic variations in regulator of G protein signaling 9 to the genetic susceptibility of heroin dependence.Mol Med Rep. 2015 May;11(5):3908-13. doi: 10.3892/mmr.2015.3210. Epub 2015 Jan 16.
• [6] Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma.Oncogene. 2015 Jan 2;34(1):94-103. doi: 10.1038/onc.2013.523. Epub 2013 Dec 9.
• [7] D2 dopamine receptors colocalize regulator of G-protein signaling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways.J Neurosci. 2005 Feb 23;25(8):2157-65. doi: 10.1523/JNEUROSCI.2840-04.2005.
• [8] The involvement of RGS9 in l-3,4-dihydroxyphenylalanine-induced dyskinesias in unilateral 6-OHDA lesion rat model.Brain Res Bull. 2011 Nov 25;86(5-6):367-72. doi: 10.1016/j.brainresbull.2011.09.016. Epub 2011 Sep 24.
• [9] Analysis of genetic variations in the RGS9 gene and antipsychotic-induced tardive dyskinesia in schizophrenia.Am J Med Genet B Neuropsychiatr Genet. 2009 Mar 5;150B(2):239-42. doi: 10.1002/ajmg.b.30796.
• [10] Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.Sci Rep. 2019 Feb 4;9(1):1219. doi: 10.1038/s41598-018-38007-2.
• [11] Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain.Synapse. 2007 May;61(5):303-9. doi: 10.1002/syn.20368.
• [12] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [13] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [18] 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.
• [19] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [21] Cordycepin inhibits the proliferation and progression of NPC by targeting the MAPK/ERK and -catenin pathways. Oncol Lett. 2022 Jan;23(1):20. doi: 10.3892/ol.2021.13138. Epub 2021 Nov 16.