Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX6K345)

• DOT Name: Glutamate receptor ionotropic, kainate 3 (GRIK3)
• Synonyms: GluK3; Excitatory amino acid receptor 5; EAA5; Glutamate receptor 7; GluR-7; GluR7
• Gene Name: GRIK3
• UniProt ID: GRIK3_HUMAN
• Pfam ID: PF01094 ; PF00060 ; PF10613
• Sequence:
  MTAPWRRLRSLVWEYWAGLLVCAFWIPDSRGMPHVIRIGGIFEYADGPNAQVMNAEEHAF
  RFSANIINRNRTLLPNTTLTYDIQRIHFHDSFEATKKACDQLALGVVAIFGPSQGSCTNA
  VQSICNALEVPHIQLRWKHHPLDNKDTFYVNLYPDYASLSHAILDLVQYLKWRSATVVYD
  DSTGLIRLQELIMAPSRYNIRLKIRQLPIDSDDSRPLLKEMKRGREFRIIFDCSHTMAAQ
  ILKQAMAMGMMTEYYHFIFTTLDLYALDLEPYRYSGVNLTGFRILNVDNPHVSAIVEKWS
  MERLQAAPRSESGLLDGVMMTDAALLYDAVHIVSVCYQRAPQMTVNSLQCHRHKAWRFGG
  RFMNFIKEAQWEGLTGRIVFNKTSGLRTDFDLDIISLKEDGLEKVGVWSPADGLNITEVA
  KGRGPNVTDSLTNRSLIVTTVLEEPFVMFRKSDRTLYGNDRFEGYCIDLLKELAHILGFS
  YEIRLVEDGKYGAQDDKGQWNGMVKELIDHKADLAVAPLTITHVREKAIDFSKPFMTLGV
  SILYRKPNGTNPSVFSFLNPLSPDIWMYVLLAYLGVSCVLFVIARFSPYEWYDAHPCNPG
  SEVVENNFTLLNSFWFGMGSLMQQGSELMPKALSTRIIGGIWWFFTLIIISSYTANLAAF
  LTVERMESPIDSADDLAKQTKIEYGAVKDGATMTFFKKSKISTFEKMWAFMSSKPSALVK
  NNEEGIQRALTADYALLMESTTIEYVTQRNCNLTQIGGLIDSKGYGIGTPMGSPYRDKIT
  IAILQLQEEDKLHIMKEKWWRGSGCPEEENKEASALGIQKIGGIFIVLAAGLVLSVLVAV
  GEFVYKLRKTAEREQRSFCSTVADEIRFSLTCQRRVKHKPQPPMMVKTDAVINMHTFNDR
  RLPGKDSMACSTSLAPVFP
• Function: Receptor for glutamate that functions as a ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. The postsynaptic actions of Glu are mediated by a variety of receptors that are named according to their selective agonists. This receptor binds domoate > kainate >> L-glutamate = quisqualate >> AMPA = NMDA.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Glutamatergic sy.pse (hsa04724)
• Reactome Pathway:
  Presynaptic function of Kainate receptors (R-HSA-500657)
  Activation of Ca-permeable Kainate Receptor (R-HSA-451308)

Molecular Interaction Atlas (MIA) of This DOT

3 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, kainate 3 (GRIK3).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glutamate receptor ionotropic, kainate 3 (GRIK3).	[9]

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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [3] 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.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] 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.
• [10] 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.