Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT85LOCJ)

• DOT Name: Glutamate receptor 1 (GRIA1)
• Synonyms: GluR-1; AMPA-selective glutamate receptor 1; GluR-A; GluR-K1; Glutamate receptor ionotropic, AMPA 1; GluA1
• Gene Name: GRIA1
• Related Disease:
  Intellectual developmental disorder, autosomal dominant 67
  Intellectual developmental disorder, autosomal recessive 76
• UniProt ID: GRIA1_HUMAN
• PDB ID: 6X5Q
• Pfam ID: PF01094 ; PF00060 ; PF10613 ; PF00497
• Sequence:
  MQHIFAFFCTGFLGAVVGANFPNNIQIGGLFPNQQSQEHAAFRFALSQLTEPPKLLPQID
  IVNISDSFEMTYRFCSQFSKGVYAIFGFYERRTVNMLTSFCGALHVCFITPSFPVDTSNQ
  FVLQLRPELQDALISIIDHYKWQKFVYIYDADRGLSVLQKVLDTAAEKNWQVTAVNILTT
  TEEGYRMLFQDLEKKKERLVVVDCESERLNAILGQIIKLEKNGIGYHYILANLGFMDIDL
  NKFKESGANVTGFQLVNYTDTIPAKIMQQWKNSDARDHTRVDWKRPKYTSALTYDGVKVM
  AEAFQSLRRQRIDISRRGNAGDCLANPAVPWGQGIDIQRALQQVRFEGLTGNVQFNEKGR
  RTNYTLHVIEMKHDGIRKIGYWNEDDKFVPAATDAQAGGDNSSVQNRTYIVTTILEDPYV
  MLKKNANQFEGNDRYEGYCVELAAEIAKHVGYSYRLEIVSDGKYGARDPDTKAWNGMVGE
  LVYGRADVAVAPLTITLVREEVIDFSKPFMSLGISIMIKKPQKSKPGVFSFLDPLAYEIW
  MCIVFAYIGVSVVLFLVSRFSPYEWHSEEFEEGRDQTTSDQSNEFGIFNSLWFSLGAFMQ
  QGCDISPRSLSGRIVGGVWWFFTLIIISSYTANLAAFLTVERMVSPIESAEDLAKQTEIA
  YGTLEAGSTKEFFRRSKIAVFEKMWTYMKSAEPSVFVRTTEEGMIRVRKSKGKYAYLLES
  TMNEYIEQRKPCDTMKVGGNLDSKGYGIATPKGSALRNPVNLAVLKLNEQGLLDKLKNKW
  WYDKGECGSGGGDSKDKTSALSLSNVAGVFYILIGGLGLAMLVALIEFCYKSRSESKRMK
  GFCLIPQQSINEAIRTSTLPRNSGAGASSGGSGENGRVVSHDFPKSMQSIPCMSHSSGMP
  LGATGL
• 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. 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.
• Tissue Specificity: Widely expressed in brain.
• 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)
  Amphetamine addiction (hsa05031)
  Nicotine addiction (hsa05033)
• Reactome Pathway:
  Activation of AMPA receptors (R-HSA-399710)
  Trafficking of AMPA receptors (R-HSA-399719)
  Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)
  Cargo concentration in the ER (R-HSA-5694530)
  Synaptic adhesion-like molecules (R-HSA-8849932)
  Long-term potentiation (R-HSA-9620244)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual developmental disorder, autosomal dominant 67	DISAB15L	Strong	Autosomal dominant	[1]
Intellectual developmental disorder, autosomal recessive 76	DISY5DCZ	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Citalopram	DM2G9AE	Approved	Glutamate receptor 1 (GRIA1) affects the response to substance of Citalopram.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Glutamate receptor 1 (GRIA1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glutamate receptor 1 (GRIA1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Glutamate receptor 1 (GRIA1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutamate receptor 1 (GRIA1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Glutamate receptor 1 (GRIA1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Glutamate receptor 1 (GRIA1).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Glutamate receptor 1 (GRIA1).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Glutamate receptor 1 (GRIA1).	[8]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Glutamate receptor 1 (GRIA1).	[9]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Glutamate receptor 1 (GRIA1).	[10]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Glutamate receptor 1 (GRIA1).	[11]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Glutamate receptor 1 (GRIA1).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Glutamate receptor 1 (GRIA1).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glutamate receptor 1 (GRIA1).	[7]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid increases the expression of Glutamate receptor 1 (GRIA1).	[15]

References

• [1] Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome. Am J Hum Genet. 2022 Jul 7;109(7):1217-1241. doi: 10.1016/j.ajhg.2022.05.009. Epub 2022 Jun 7.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] 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.
• [4] 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.
• [5] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [10] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [11] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [12] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [13] 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.
• [14] 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.
• [15] Profiling transcriptomes of human SH-SY5Y neuroblastoma cells exposed to maleic acid. PeerJ. 2017 Apr 5;5:e3175.
• [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.