Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV7ZA9O)

• DOT Name: Glutamate receptor ionotropic, NMDA 2C (GRIN2C)
• Synonyms: GluN2C; Glutamate receptor subunit epsilon-3; N-methyl D-aspartate receptor subtype 2C; NMDAR2C; NR2C
• Gene Name: GRIN2C
• UniProt ID: NMDE3_HUMAN
• PDB ID: 8E92; 8E93; 8E94; 8E97; 8E98; 8E99
• Pfam ID: PF01094 ; PF00060 ; PF10613 ; PF10565 ; PF00497
• Sequence:
  MGGALGPALLLTSLFGAWAGLGPGQGEQGMTVAVVFSSSGPPQAQFRARLTPQSFLDLPL
  EIQPLTVGVNTTNPSSLLTQICGLLGAAHVHGIVFEDNVDTEAVAQILDFISSQTHVPIL
  SISGGSAVVLTPKEPGSAFLQLGVSLEQQLQVLFKVLEEYDWSAFAVITSLHPGHALFLE
  GVRAVADASHVSWRLLDVVTLELGPGGPRARTQRLLRQLDAPVFVAYCSREEAEVLFAEA
  AQAGLVGPGHVWLVPNLALGSTDAPPATFPVGLISVVTESWRLSLRQKVRDGVAILALGA
  HSYWRQHGTLPAPAGDCRVHPGPVSPAREAFYRHLLNVTWEGRDFSFSPGGYLVQPTMVV
  IALNRHRLWEMVGRWEHGVLYMKYPVWPRYSASLQPVVDSRHLTVATLEERPFVIVESPD
  PGTGGCVPNTVPCRRQSNHTFSSGDVAPYTKLCCKGFCIDILKKLARVVKFSYDLYLVTN
  GKHGKRVRGVWNGMIGEVYYKRADMAIGSLTINEERSEIVDFSVPFVETGISVMVARSNG
  TVSPSAFLEPYSPAVWVMMFVMCLTVVAITVFMFEYFSPVSYNQNLTRGKKSGGPAFTIG
  KSVWLLWALVFNNSVPIENPRGTTSKIMVLVWAFFAVIFLASYTANLAAFMIQEQYIDTV
  SGLSDKKFQRPQDQYPPFRFGTVPNGSTERNIRSNYRDMHTHMVKFNQRSVEDALTSLKM
  GKLDAFIYDAAVLNYMAGKDEGCKLVTIGSGKVFATTGYGIAMQKDSHWKRAIDLALLQF
  LGDGETQKLETVWLSGICQNEKNEVMSSKLDIDNMAGVFYMLLVAMGLALLVFAWEHLVY
  WKLRHSVPNSSQLDFLLAFSRGIYSCFSGVQSLASPPRQASPDLTASSAQASVLKMLQAA
  RDMVTTAGVSSSLDRATRTIENWGGGRRAPPPSPCPTPRSGPSPCLPTPDPPPEPSPTGW
  GPPDGGRAALVRRAPQPPGRPPTPGPPLSDVSRVSRRPAWEARWPVRTGHCGRHLSASER
  PLSPARCHYSSFPRADRSGRPFLPLFPELEDLPLLGPEQLARREALLHAAWARGSRPRHA
  SLPSSVAEAFARPSSLPAGCTGPACARPDGHSACRRLAQAQSMCLPIYREACQEGEQAGA
  PAWQHRQHVCLHAHAHLPFCWGAVCPHLPPCASHGSWLSGAWGPLGHRGRTLGLGTGYRD
  SGGLDEISRVARGTQGFPGPCTWRRISSLESEV
• 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 (Probable). Plays a role in regulating the balance between excitatory and inhibitory activity of pyramidal neurons in the prefrontal cortex. Contributes to the slow phase of excitatory postsynaptic current, long-term synaptic potentiation, and learning.
• Tissue Specificity: Mainly expressed in brain with predominant expression is in the cerebellum, also present in the hippocampus, amygdala, caudate nucleus, corpus callosum, subthalamic nuclei and thalamus. Detected in the heart, skeletal muscle and pancreas.
• KEGG Pathway:
  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)
  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)
• Reactome Pathway:
  Neurexins and neuroligins (R-HSA-6794361)
  Synaptic adhesion-like molecules (R-HSA-8849932)
  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

1 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 Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[5]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[3]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[6]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[7]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[11]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the expression of Glutamate receptor ionotropic, NMDA 2C (GRIN2C).	[12]

References

• [1] 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.
• [2] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [6] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [7] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] 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.
• [12] 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.