Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL5EIPA)

• DOT Name: Glutamate receptor ionotropic, kainate 4 (GRIK4)
• Synonyms: GluK4; Excitatory amino acid receptor 1; EAA1; Glutamate receptor KA-1; KA1
• Gene Name: GRIK4
• UniProt ID: GRIK4_HUMAN
• Pfam ID: PF01094 ; PF00060 ; PF10613
• Sequence:
  MPRVSAPLVLLPAWLVMVACSPHSLRIAAILDDPMECSRGERLSITLAKNRINRAPERLG
  KAKVEVDIFELLRDSEYETAETMCQILPKGVVAVLGPSSSPASSSIISNICGEKEVPHFK
  VAPEEFVKFQFQRFTTLNLHPSNTDISVAVAGILNFFNCTTACLICAKAECLLNLEKLLR
  QFLISKDTLSVRMLDDTRDPTPLLKEIRDDKTATIIIHANASMSHTILLKAAELGMVSAY
  YTYIFTNLEFSLQRMDSLVDDRVNILGFSIFNQSHAFFQEFAQSLNQSWQENCDHVPFTG
  PALSSALLFDAVYAVVTAVQELNRSQEIGVKPLSCGSAQIWQHGTSLMNYLRMVELEGLT
  GHIEFNSKGQRSNYALKILQFTRNGFRQIGQWHVAEGLSMDSHLYASNISDTLFNTTLVV
  TTILENPYLMLKGNHQEMEGNDRYEGFCVDMLKELAEILRFNYKIRLVGDGVYGVPEANG
  TWTGMVGELIARKADLAVAGLTITAEREKVIDFSKPFMTLGISILYRVHMGRKPGYFSFL
  DPFSPGVWLFMLLAYLAVSCVLFLVARLTPYEWYSPHPCAQGRCNLLVNQYSLGNSLWFP
  VGGFMQQGSTIAPRALSTRCVSGVWWAFTLIIISSYTANLAAFLTVQRMDVPIESVDDLA
  DQTAIEYGTIHGGSSMTFFQNSRYQTYQRMWNYMYSKQPSVFVKSTEEGIARVLNSNYAF
  LLESTMNEYYRQRNCNLTQIGGLLDTKGYGIGMPVGSVFRDEFDLAILQLQENNRLEILK
  RKWWEGGKCPKEEDHRAKGLGMENIGGIFVVLICGLIVAIFMAMLEFLWTLRHSEATEVS
  VCQEMVTELRSIILCQDSIHPRRRRAAVPPPRPPIPEERRPRGTATLSNGKLCGAGEPDQ
  LAQRLAQEAALVARGCTHIRVCPECRRFQGLRARPSPARSEESLEWEKTTNSSEPE
• Function: Receptor for glutamate. 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.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Glutamatergic sy.pse (hsa04724)
• Reactome Pathway: Activation of Ca-permeable Kainate Receptor (R-HSA-451308)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Citalopram	DM2G9AE	Approved	Glutamate receptor ionotropic, kainate 4 (GRIK4) increases the response of Citalopram.	[6]

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 4 (GRIK4).	[1]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Glutamate receptor ionotropic, kainate 4 (GRIK4).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Glutamate receptor ionotropic, kainate 4 (GRIK4).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glutamate receptor ionotropic, kainate 4 (GRIK4).	[2]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Glutamate receptor ionotropic, kainate 4 (GRIK4).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glutamate receptor ionotropic, kainate 4 (GRIK4).	[5]

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] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [3] 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.
• [4] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [5] 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.
• [6] Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. Am J Psychiatry. 2007 Aug;164(8):1181-8. doi: 10.1176/appi.ajp.2007.06111790.