Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ41U3D)

• DOT Name: Glutamate receptor ionotropic, kainate 2 (GRIK2)
• Synonyms: GluK2; Excitatory amino acid receptor 4; EAA4; Glutamate receptor 6; GluR-6; GluR6
• Gene Name: GRIK2
• Related Disease:
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal recessive 6
  Neurodevelopmental disorder with impaired language and ataxia and with or without seizures
  Autosomal recessive non-syndromic intellectual disability
• UniProt ID: GRIK2_HUMAN
• PDB ID: 3QXM; 5CMM
• Pfam ID: PF01094 ; PF00060 ; PF10613
• Sequence:
  MKIIFPILSNPVFRRTVKLLLCLLWIGYSQGTTHVLRFGGIFEYVESGPMGAEELAFRFA
  VNTINRNRTLLPNTTLTYDTQKINLYDSFEASKKACDQLSLGVAAIFGPSHSSSANAVQS
  ICNALGVPHIQTRWKHQVSDNKDSFYVSLYPDFSSLSRAILDLVQFFKWKTVTVVYDDST
  GLIRLQELIKAPSRYNLRLKIRQLPADTKDAKPLLKEMKRGKEFHVIFDCSHEMAAGILK
  QALAMGMMTEYYHYIFTTLDLFALDVEPYRYSGVNMTGFRILNTENTQVSSIIEKWSMER
  LQAPPKPDSGLLDGFMTTDAALMYDAVHVVSVAVQQFPQMTVSSLQCNRHKPWRFGTRFM
  SLIKEAHWEGLTGRITFNKTNGLRTDFDLDVISLKEEGLEKIGTWDPASGLNMTESQKGK
  PANITDSLSNRSLIVTTILEEPYVLFKKSDKPLYGNDRFEGYCIDLLRELSTILGFTYEI
  RLVEDGKYGAQDDANGQWNGMVRELIDHKADLAVAPLAITYVREKVIDFSKPFMTLGISI
  LYRKPNGTNPGVFSFLNPLSPDIWMYILLAYLGVSCVLFVIARFSPYEWYNPHPCNPDSD
  VVENNFTLLNSFWFGVGALMQQGSELMPKALSTRIVGGIWWFFTLIIISSYTANLAAFLT
  VERMESPIDSADDLAKQTKIEYGAVEDGATMTFFKKSKISTYDKMWAFMSSRRQSVLVKS
  NEEGIQRVLTSDYAFLMESTTIEFVTQRNCNLTQIGGLIDSKGYGVGTPMGSPYRDKITI
  AILQLQEEGKLHMMKEKWWRGNGCPEEESKEASALGVQNIGGIFIVLAAGLVLSVFVAVG
  EFLYKSKKNAQLEKRSFCSAMVEELRMSLKCQRRLKHKPQAPVIVKTEEVINMHTFNDRR
  LPGKETMA
• Function: Ionotropic glutamate receptor. 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. Modulates cell surface expression of NETO2; Independent of its ionotropic glutamate receptor activity, acts as a thermoreceptor conferring sensitivity to cold temperatures. Functions in dorsal root ganglion neurons.
• Tissue Specificity: Expression is higher in cerebellum than in cerebral cortex.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Glutamatergic sy.pse (hsa04724)
• Reactome Pathway:
  Activation of Ca-permeable Kainate Receptor (R-HSA-451308)
  Activation of Na-permeable kainate receptors (R-HSA-451307)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Intellectual disability, autosomal recessive 6	DISVZWE0	Definitive	Autosomal recessive	[2]
Neurodevelopmental disorder with impaired language and ataxia and with or without seizures	DISKP15X	Strong	Autosomal dominant	[3]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Glutamate receptor ionotropic, kainate 2 (GRIK2) increases the Suicidal ideation ADR of Aspirin.	[15]
Citalopram	DM2G9AE	Approved	Glutamate receptor ionotropic, kainate 2 (GRIK2) affects the response to substance of Citalopram.	[16]

9 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 ionotropic, kainate 2 (GRIK2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutamate receptor ionotropic, kainate 2 (GRIK2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glutamate receptor ionotropic, kainate 2 (GRIK2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Glutamate receptor ionotropic, kainate 2 (GRIK2).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Glutamate receptor ionotropic, kainate 2 (GRIK2).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Glutamate receptor ionotropic, kainate 2 (GRIK2).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Glutamate receptor ionotropic, kainate 2 (GRIK2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glutamate receptor ionotropic, kainate 2 (GRIK2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glutamate receptor ionotropic, kainate 2 (GRIK2).	[14]

2 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, kainate 2 (GRIK2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Glutamate receptor ionotropic, kainate 2 (GRIK2).	[13]

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] A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. Am J Hum Genet. 2007 Oct;81(4):792-8. doi: 10.1086/521275. Epub 2007 Aug 31.
• [3] Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders. Am J Hum Genet. 2021 Sep 2;108(9):1692-1709. doi: 10.1016/j.ajhg.2021.07.007. Epub 2021 Aug 9.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Genetic markers of suicidal ideation emerging during citalopram treatment of major depression. Am J Psychiatry. 2007 Oct;164(10):1530-8. doi: 10.1176/appi.ajp.2007.06122018.
• [16] 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.