Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5N1WB7)

• DOT Name: Glutamate receptor 2 (GRIA2)
• Synonyms: GluR-2; AMPA-selective glutamate receptor 2; GluR-B; GluR-K2; Glutamate receptor ionotropic, AMPA 2; GluA2
• Gene Name: GRIA2
• Related Disease: Neurodevelopmental disorder with language impairment and behavioral abnormalities
• UniProt ID: GRIA2_HUMAN
• PDB ID: 2WJW; 2WJX; 2XHD; 3R7X; 3RN8; 3RNN; 3UA8; 5H8S; 5YBF; 5YBG; 5ZG0; 5ZG1; 5ZG2; 5ZG3; 7F3O
• Pfam ID: PF01094 ; PF00060 ; PF10613 ; PF00497
• Sequence:
  MQKIMHISVLLSPVLWGLIFGVSSNSIQIGGLFPRGADQEYSAFRVGMVQFSTSEFRLTP
  HIDNLEVANSFAVTNAFCSQFSRGVYAIFGFYDKKSVNTITSFCGTLHVSFITPSFPTDG
  THPFVIQMRPDLKGALLSLIEYYQWDKFAYLYDSDRGLSTLQAVLDSAAEKKWQVTAINV
  GNINNDKKDEMYRSLFQDLELKKERRVILDCERDKVNDIVDQVITIGKHVKGYHYIIANL
  GFTDGDLLKIQFGGANVSGFQIVDYDDSLVSKFIERWSTLEEKEYPGAHTTTIKYTSALT
  YDAVQVMTEAFRNLRKQRIEISRRGNAGDCLANPAVPWGQGVEIERALKQVQVEGLSGNI
  KFDQNGKRINYTINIMELKTNGPRKIGYWSEVDKMVVTLTELPSGNDTSGLENKTVVVTT
  ILESPYVMMKKNHEMLEGNERYEGYCVDLAAEIAKHCGFKYKLTIVGDGKYGARDADTKI
  WNGMVGELVYGKADIAIAPLTITLVREEVIDFSKPFMSLGISIMIKKPQKSKPGVFSFLD
  PLAYEIWMCIVFAYIGVSVVLFLVSRFSPYEWHTEEFEDGRETQSSESTNEFGIFNSLWF
  SLGAFMQQGCDISPRSLSGRIVGGVWWFFTLIIISSYTANLAAFLTVERMVSPIESAEDL
  SKQTEIAYGTLDSGSTKEFFRRSKIAVFDKMWTYMRSAEPSVFVRTTAEGVARVRKSKGK
  YAYLLESTMNEYIEQRKPCDTMKVGGNLDSKGYGIATPKGSSLRNAVNLAVLKLNEQGLL
  DKLKNKWWYDKGECGSGGGDSKEKTSALSLSNVAGVFYILVGGLGLAMLVALIEFCYKSR
  AEAKRMKVAKNAQNINPSSSQNSQNFATYKEGYNVYGIESVKI
• Function: Receptor for glutamate that functions as a ligand-gated ion channel in the central nervous system. It plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. Through complex formation with NSG1, GRIP1 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Nicotine addiction (hsa05033)
• Reactome Pathway:
  Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)
  MECP2 regulates neuronal receptors and channels (R-HSA-9022699)
  Long-term potentiation (R-HSA-9620244)
  Activation of AMPA receptors (R-HSA-399710)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with language impairment and behavioral abnormalities	DIS98L5N	Definitive	Autosomal dominant	[1]

12 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 Glutamate receptor 2 (GRIA2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutamate receptor 2 (GRIA2).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutamate receptor 2 (GRIA2).	[4]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Glutamate receptor 2 (GRIA2).	[5]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Glutamate receptor 2 (GRIA2).	[6]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Glutamate receptor 2 (GRIA2).	[7]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Glutamate receptor 2 (GRIA2).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Glutamate receptor 2 (GRIA2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glutamate receptor 2 (GRIA2).	[9]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Glutamate receptor 2 (GRIA2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glutamate receptor 2 (GRIA2).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Glutamate receptor 2 (GRIA2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Glutamate receptor 2 (GRIA2).	[11]

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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] 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.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [8] Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates. J Neurochem. 2005 Dec;95(6):1785-93. doi: 10.1111/j.1471-4159.2005.03517.x.
• [9] Disruption of glutamate neurotransmitter transmission is modulated by SNAP-25 in benzo[a]pyrene-induced neurotoxic effects. Toxicology. 2017 Jun 1;384:11-22. doi: 10.1016/j.tox.2017.03.021. Epub 2017 Apr 19.
• [10] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [11] 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.
• [12] 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.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.