Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTP0KN8)

• DOT Name: Glutamate receptor ionotropic, NMDA 2A (GRIN2A)
• Synonyms: GluN2A; Glutamate receptor subunit epsilon-1; N-methyl D-aspartate receptor subtype 2A; NMDAR2A; NR2A; hNR2A
• Gene Name: GRIN2A
• Related Disease:
  Complex neurodevelopmental disorder
  Landau-Kleffner syndrome
  Childhood epilepsy with centrotemporal spikes
  Continuous spikes and waves during sleep
  Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
  Rolandic epilepsy-speech dyspraxia syndrome
• UniProt ID: NMDE1_HUMAN
• PDB ID: 3NFL; 5H8F; 5H8H; 5H8N; 5H8Q; 5I2K; 5I2N; 5KCJ; 5KDT; 5TP9; 5TPA; 6IRA; 6IRF; 6IRG; 6IRH; 7EOQ; 7EOR; 7EOS; 7EOT; 7EOU; 7EU7; 8E99
• Pfam ID: PF01094 ; PF00060 ; PF10613 ; PF10565 ; PF00497
• Sequence:
  MGRVGYWTLLVLPALLVWRGPAPSAAAEKGPPALNIAVMLGHSHDVTERELRTLWGPEQA
  AGLPLDVNVVALLMNRTDPKSLITHVCDLMSGARIHGLVFGDDTDQEAVAQMLDFISSHT
  FVPILGIHGGASMIMADKDPTSTFFQFGASIQQQATVMLKIMQDYDWHVFSLVTTIFPGY
  REFISFVKTTVDNSFVGWDMQNVITLDTSFEDAKTQVQLKKIHSSVILLYCSKDEAVLIL
  SEARSLGLTGYDFFWIVPSLVSGNTELIPKEFPSGLISVSYDDWDYSLEARVRDGIGILT
  TAASSMLEKFSYIPEAKASCYGQMERPEVPMHTLHPFMVNVTWDGKDLSFTEEGYQVHPR
  LVVIVLNKDREWEKVGKWENHTLSLRHAVWPRYKSFSDCEPDDNHLSIVTLEEAPFVIVE
  DIDPLTETCVRNTVPCRKFVKINNSTNEGMNVKKCCKGFCIDILKKLSRTVKFTYDLYLV
  TNGKHGKKVNNVWNGMIGEVVYQRAVMAVGSLTINEERSEVVDFSVPFVETGISVMVSRS
  NGTVSPSAFLEPFSASVWVMMFVMLLIVSAIAVFVFEYFSPVGYNRNLAKGKAPHGPSFT
  IGKAIWLLWGLVFNNSVPVQNPKGTTSKIMVSVWAFFAVIFLASYTANLAAFMIQEEFVD
  QVTGLSDKKFQRPHDYSPPFRFGTVPNGSTERNIRNNYPYMHQYMTKFNQKGVEDALVSL
  KTGKLDAFIYDAAVLNYKAGRDEGCKLVTIGSGYIFATTGYGIALQKGSPWKRQIDLALL
  QFVGDGEMEELETLWLTGICHNEKNEVMSSQLDIDNMAGVFYMLAAAMALSLITFIWEHL
  FYWKLRFCFTGVCSDRPGLLFSISRGIYSCIHGVHIEEKKKSPDFNLTGSQSNMLKLLRS
  AKNISSMSNMNSSRMDSPKRAADFIQRGSLIMDMVSDKGNLMYSDNRSFQGKESIFGDNM
  NELQTFVANRQKDNLNNYVFQGQHPLTLNESNPNTVEVAVSTESKANSRPRQLWKKSVDS
  IRQDSLSQNPVSQRDEATAENRTHSLKSPRYLPEEMAHSDISETSNRATCHREPDNSKNH
  KTKDNFKRSVASKYPKDCSEVERTYLKTKSSSPRDKIYTIDGEKEPGFHLDPPQFVENVT
  LPENVDFPDPYQDPSENFRKGDSTLPMNRNPLHNEEGLSNNDQYKLYSKHFTLKDKGSPH
  SETSERYRQNSTHCRSCLSNMPTYSGHFTMRSPFKCDACLRMGNLYDIDEDQMLQETGNP
  ATGEQVYQQDWAQNNALQLQKNKLRISRQHSYDNIVDKPRELDLSRPSRSISLKDRERLL
  EGNFYGSLFSVPSSKLSGKKSSLFPQGLEDSKRSKSLLPDHTSDNPFLHSHRDDQRLVIG
  RCPSDPYKHSLPSQAVNDSYLRSSLRSTASYCSRDSRGHNDVYISEHVMPYAANKNNMYS
  TPRVLNSCSNRRVYKKMPSIESDV
• Function: Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+). Sensitivity to glutamate and channel kinetics depend on the subunit composition; channels containing GRIN1 and GRIN2A have lower sensitivity to glutamate and faster deactivation kinetics than channels formed by GRIN1 and GRIN2B. Contributes to the slow phase of excitatory postsynaptic current, long-term synaptic potentiation, and learning.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Glutamatergic sy.pse (hsa04724)
  Dopaminergic sy.pse (hsa04728)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Nicotine addiction (hsa05033)
  Alcoholism (hsa05034)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Neurexins and neuroligins (R-HSA-6794361)
  Synaptic adhesion-like molecules (R-HSA-8849932)
  MECP2 regulates neuronal receptors and channels (R-HSA-9022699)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324)
  Long-term potentiation (R-HSA-9620244)
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Landau-Kleffner syndrome	DIS6IUH6	Definitive	Autosomal dominant	[2]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Supportive	Autosomal dominant	[3]
Continuous spikes and waves during sleep	DIS8OAI7	Supportive	Autosomal dominant	[4]
Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation	DIS4QCTX	Supportive	Autosomal dominant	[5]
Rolandic epilepsy-speech dyspraxia syndrome	DISWM45T	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Glutamate receptor ionotropic, NMDA 2A (GRIN2A) increases the Metabolic disorder ADR of Chlorothiazide.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[10]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[12]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[6]

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 increases the methylation of Glutamate receptor ionotropic, NMDA 2A (GRIN2A).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013 Sep;45(9):1073-6. doi: 10.1038/ng.2727. Epub 2013 Aug 11.
• [3] Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013 Sep;45(9):1067-72. doi: 10.1038/ng.2728. Epub 2013 Aug 11.
• [4] GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet. 2013 Sep;45(9):1061-6. doi: 10.1038/ng.2726. Epub 2013 Aug 11.
• [5] Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010 Nov;42(11):1021-6. doi: 10.1038/ng.677. Epub 2010 Oct 3.
• [6] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] THC Treatment Alters Glutamate Receptor Gene Expression in Human Stem Cell-Derived Neurons. Mol Neuropsychiatry. 2017 Nov;3(2):73-84. doi: 10.1159/000477762. Epub 2017 Jul 20.
• [11] Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres. Int J Mol Sci. 2020 Aug 3;21(15):5564. doi: 10.3390/ijms21155564.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] 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.