Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQS9GYY)

• DOT Name: Glutamate receptor ionotropic, NMDA 3A (GRIN3A)
• Synonyms: GluN3A; N-methyl-D-aspartate receptor subtype 3A; NMDAR3A; NR3A; NMDAR-L
• Gene Name: GRIN3A
• Related Disease:
  Delirium
  Alzheimer disease
  Aural atresia, congenital
  Bipolar disorder
  Cerebral palsy
  Congenital disorder of glycosylation
  Drug dependence
  Erectile dysfunction
  Heroin dependence
  Huntington disease
  Nicotine dependence
  Autoimmune disease
  Schizophrenia
  Nervous system disease
• UniProt ID: NMD3A_HUMAN
• Pfam ID: PF01094 ; PF00060 ; PF10613 ; PF00497
• Sequence:
  MRRLSLWWLLSRVCLLLPPPCALVLAGVPSSSSHPQPCQILKRIGHAVRVGAVHLQPWTT
  APRAASRAPDDSRAGAQRDEPEPGTRRSPAPSPGARWLGSTLHGRGPPGSRKPGEGARAE
  ALWPRDALLFAVDNLNRVEGLLPYNLSLEVVMAIEAGLGDLPLLPFSSPSSPWSSDPFSF
  LQSVCHTVVVQGVSALLAFPQSQGEMMELDLVSLVLHIPVISIVRHEFPRESQNPLHLQL
  SLENSLSSDADVTVSILTMNNWYNFSLLLCQEDWNITDFLLLTQNNSKFHLGSIINITAN
  LPSTQDLLSFLQIQLESIKNSTPTVVMFGCDMESIRRIFEITTQFGVMPPELRWVLGDSQ
  NVEELRTEGLPLGLIAHGKTTQSVFEHYVQDAMELVARAVATATMIQPELALIPSTMNCM
  EVETTNLTSGQYLSRFLANTTFRGLSGSIRVKGSTIVSSENNFFIWNLQHDPMGKPMWTR
  LGSWQGGKIVMDYGIWPEQAQRHKTHFQHPSKLHLRVVTLIEHPFVFTREVDDEGLCPAG
  QLCLDPMTNDSSTLDSLFSSLHSSNDTVPIKFKKCCYGYCIDLLEKIAEDMNFDFDLYIV
  GDGKYGAWKNGHWTGLVGDLLRGTAHMAVTSFSINTARSQVIDFTSPFFSTSLGILVRTR
  DTAAPIGAFMWPLHWTMWLGIFVALHITAVFLTLYEWKSPFGLTPKGRNRSKVFSFSSAL
  NICYALLFGRTVAIKPPKCWTGRFLMNLWAIFCMFCLSTYTANLAAVMVGEKIYEELSGI
  HDPKLHHPSQGFRFGTVRESSAEDYVRQSFPEMHEYMRRYNVPATPDGVEYLKNDPEKLD
  AFIMDKALLDYEVSIDADCKLLTVGKPFAIEGYGIGLPPNSPLTANISELISQYKSHGFM
  DMLHDKWYRVVPCGKRSFAVTETLQMGIKHFSGLFVLLCIGFGLSILTTIGEHIVYRLLL
  PRIKNKSKLQYWLHTSQRLHRAINTSFIEEKQQHFKTKRVEKRSNVGPRQLTVWNTSNLS
  HDNRRKYIFSDEEGQNQLGIRIHQDIPLPPRRRELPALRTTNGKADSLNVSRNSVMQELS
  ELEKQIQVIRQELQLAVSRKTELEEYQRTSRTCES
• Function: NMDA receptor subtype of glutamate-gated ion channels with reduced single-channel conductance, low calcium permeability and low voltage-dependent sensitivity to magnesium. Mediated by glycine. During the development of neural circuits, plays a role in the synaptic refinement period, restricting spine maturation and growth. By competing with GIT1 interaction with ARHGEF7/beta-PIX, may reduce GIT1/ARHGEF7-regulated local activation of RAC1, hence affecting signaling and limiting the maturation and growth of inactive synapses. May also play a role in PPP2CB-NMDAR mediated signaling mechanism.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Glutamatergic sy.pse (hsa04724)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Nicotine addiction (hsa05033)
  Alcoholism (hsa05034)
• Reactome Pathway: Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Delirium	DIS2OKP1	Definitive	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Aural atresia, congenital	DISCP7UV	Strong	Genetic Variation	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Cerebral palsy	DIS82ODL	Strong	Biomarker	[5]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[6]
Drug dependence	DIS9IXRC	Strong	Altered Expression	[7]
Erectile dysfunction	DISD8MTH	Strong	Biomarker	[8]
Heroin dependence	DISQ1H57	Strong	Genetic Variation	[9]
Huntington disease	DISQPLA4	Strong	Biomarker	[10]
Nicotine dependence	DISZD9W7	Strong	Genetic Variation	[11]
Autoimmune disease	DISORMTM	moderate	Biomarker	[12]
Schizophrenia	DISSRV2N	moderate	Biomarker	[13]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[14]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Glutamate receptor ionotropic, NMDA 3A (GRIN3A) increases the Metabolic disorder ADR of Chlorothiazide.	[21]
Citalopram	DM2G9AE	Approved	Glutamate receptor ionotropic, NMDA 3A (GRIN3A) affects the response to substance of Citalopram.	[8]
Interferon gamma-1b	DMWUMRL	Approved	Glutamate receptor ionotropic, NMDA 3A (GRIN3A) increases the Agitation ADR of Interferon gamma-1b.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Glutamate receptor ionotropic, NMDA 3A (GRIN3A).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Glutamate receptor ionotropic, NMDA 3A (GRIN3A).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Glutamate receptor ionotropic, NMDA 3A (GRIN3A).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Glutamate receptor ionotropic, NMDA 3A (GRIN3A).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Glutamate receptor ionotropic, NMDA 3A (GRIN3A).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glutamate receptor ionotropic, NMDA 3A (GRIN3A).	[19]

References

• [1] The assessment of the T102C polymorphism of the 5HT2a receptor gene, 3723G/A polymorphism of the NMDA receptor 3A subunit gene (GRIN3A) and 421C/A polymorphism of the NMDA receptor 2B subunit gene (GRIN2B) among cardiac surgery patients with and without delirium.Gen Hosp Psychiatry. 2014 Nov-Dec;36(6):753-6. doi: 10.1016/j.genhosppsych.2014.06.002. Epub 2014 Jun 14.
• [2] Genetic variation in N-methyl-D-aspartate receptor subunit NR3A but not NR3B influences susceptibility to Alzheimer's disease.Dement Geriatr Cogn Disord. 2009;28(6):521-7. doi: 10.1159/000254757. Epub 2009 Dec 10.
• [3] Association between GRIN3A gene polymorphism in Kawasaki disease and coronary artery aneurysms in Taiwanese children.PLoS One. 2013 Nov 22;8(11):e81384. doi: 10.1371/journal.pone.0081384. eCollection 2013.
• [4] NR3A NMDA receptor subunit mRNA expression in schizophrenia, depression and bipolar disorder.Schizophr Res. 2004 Dec 1;71(2-3):361-70. doi: 10.1016/j.schres.2004.02.016.
• [5] Association of polymorphisms in neuroprotection and oxidative stress genes and neurodevelopmental outcomes after preterm birth.Obstet Gynecol. 2012 Sep;120(3):542-50. doi: 10.1097/AOG.0b013e318265f232.
• [6] N-Glycosylation Regulates the Trafficking and Surface Mobility of GluN3A-Containing NMDA Receptors.Front Mol Neurosci. 2018 Jun 4;11:188. doi: 10.3389/fnmol.2018.00188. eCollection 2018.
• [7] Expression of NMDA receptor subunits in human blood lymphocytes: A peripheral biomarker in online computer game addiction.J Behav Addict. 2018 Jun 1;7(2):260-268. doi: 10.1556/2006.7.2018.35. Epub 2018 May 23.
• [8] Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients. Neuropsychopharmacology. 2009 Jun;34(7):1819-28. doi: 10.1038/npp.2009.4. Epub 2009 Mar 18.
• [9] Association between genetic variations of NMDA receptor NR3 subfamily genes and heroin addiction in male Han Chinese.Neurosci Lett. 2016 Sep 19;631:122-125. doi: 10.1016/j.neulet.2016.08.025. Epub 2016 Aug 16.
• [10] RNAi-Based GluN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin.Mol Ther. 2018 Aug 1;26(8):1965-1972. doi: 10.1016/j.ymthe.2018.05.013. Epub 2018 Jun 15.
• [11] Demonstration of critical role of GRIN3A in nicotine dependence through both genetic association and molecular functional studies.Addict Biol. 2020 Jan;25(1):e12718. doi: 10.1111/adb.12718. Epub 2019 Feb 11.
• [12] Immuno-Pharmacological Characterization of Presynaptic GluN3A-Containing NMDA Autoreceptors: Relevance to Anti-NMDA Receptor Autoimmune Diseases.Mol Neurobiol. 2019 Sep;56(9):6142-6155. doi: 10.1007/s12035-019-1511-8. Epub 2019 Feb 7.
• [13] Polymorphisms in MicroRNA Genes And Genes Involving in NMDAR Signaling and Schizophrenia: A Case-Control Study in Chinese Han Population.Sci Rep. 2015 Aug 10;5:12984. doi: 10.1038/srep12984.
• [14] Influence of the NR3A subunit on NMDA receptor functions.Prog Neurobiol. 2010 May;91(1):23-37. doi: 10.1016/j.pneurobio.2010.01.004. Epub 2010 Jan 25.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] 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.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.
• [22] Genetic and clinical predictors of sexual dysfunction in citalopram-treated depressed patients. Neuropsychopharmacology. 2009 Jun;34(7):1819-28. doi: 10.1038/npp.2009.4. Epub 2009 Mar 18.
• [23] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.