Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT34CNBR)

• DOT Name: Glutamate receptor 3 (GRIA3)
• Synonyms: GluR-3; AMPA-selective glutamate receptor 3; GluR-C; GluR-K3; Glutamate receptor ionotropic, AMPA 3; GluA3
• Gene Name: GRIA3
• Related Disease:
  Syndromic X-linked intellectual disability 94
  X-linked complex neurodevelopmental disorder
  Obsolete X-linked intellectual disability due to GRIA3 anomalies
• UniProt ID: GRIA3_HUMAN
• Pfam ID: PF01094 ; PF00060 ; PF10613 ; PF00497
• Sequence:
  MARQKKMGQSVLRAVFFLVLGLLGHSHGGFPNTISIGGLFMRNTVQEHSAFRFAVQLYNT
  NQNTTEKPFHLNYHVDHLDSSNSFSVTNAFCSQFSRGVYAIFGFYDQMSMNTLTSFCGAL
  HTSFVTPSFPTDADVQFVIQMRPALKGAILSLLGHYKWEKFVYLYDTERGFSILQAIMEA
  AVQNNWQVTARSVGNIKDVQEFRRIIEEMDRRQEKRYLIDCEVERINTILEQVVILGKHS
  RGYHYMLANLGFTDILLERVMHGGANITGFQIVNNENPMVQQFIQRWVRLDEREFPEAKN
  APLKYTSALTHDAILVIAEAFRYLRRQRVDVSRRGSAGDCLANPAVPWSQGIDIERALKM
  VQVQGMTGNIQFDTYGRRTNYTIDVYEMKVSGSRKAGYWNEYERFVPFSDQQISNDSASS
  ENRTIVVTTILESPYVMYKKNHEQLEGNERYEGYCVDLAYEIAKHVRIKYKLSIVGDGKY
  GARDPETKIWNGMVGELVYGRADIAVAPLTITLVREEVIDFSKPFMSLGISIMIKKPQKS
  KPGVFSFLDPLAYEIWMCIVFAYIGVSVVLFLVSRFSPYEWHLEDNNEEPRDPQSPPDPP
  NEFGIFNSLWFSLGAFMQQGCDISPRSLSGRIVGGVWWFFTLIIISSYTANLAAFLTVER
  MVSPIESAEDLAKQTEIAYGTLDSGSTKEFFRRSKIAVYEKMWSYMKSAEPSVFTKTTAD
  GVARVRKSKGKFAFLLESTMNEYIEQRKPCDTMKVGGNLDSKGYGVATPKGSALRNAVNL
  AVLKLNEQGLLDKLKNKWWYDKGECGSGGGDSKDKTSALSLSNVAGVFYILVGGLGLAMM
  VALIEFCYKSRAESKRMKLTKNTQNFKPAPATNTQNYATYREGYNVYGTESVKI
• 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. 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.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Amphetamine addiction (hsa05031)
  Nicotine addiction (hsa05033)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  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)
  Synaptic adhesion-like molecules (R-HSA-8849932)
  Activation of AMPA receptors (R-HSA-399710)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Syndromic X-linked intellectual disability 94	DISE6E8H	Definitive	X-linked recessive	[1]
X-linked complex neurodevelopmental disorder	DISI3QE9	Definitive	X-linked	[2]
Obsolete X-linked intellectual disability due to GRIA3 anomalies	DISZSOUJ	Supportive	X-linked	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Glutamate receptor 3 (GRIA3) increases the Suicidal ideation ADR of Aspirin.	[16]
Citalopram	DM2G9AE	Approved	Glutamate receptor 3 (GRIA3) affects the response to substance of Citalopram.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Glutamate receptor 3 (GRIA3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutamate receptor 3 (GRIA3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glutamate receptor 3 (GRIA3).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Glutamate receptor 3 (GRIA3).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Glutamate receptor 3 (GRIA3).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Glutamate receptor 3 (GRIA3).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Glutamate receptor 3 (GRIA3).	[10]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Glutamate receptor 3 (GRIA3).	[11]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Glutamate receptor 3 (GRIA3).	[12]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Glutamate receptor 3 (GRIA3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glutamate receptor 3 (GRIA3).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Glutamate receptor 3 (GRIA3).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glutamate receptor 3 (GRIA3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Glutamate receptor 3 (GRIA3).	[9]

References

• [1] Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18163-8. doi: 10.1073/pnas.0708699104. Epub 2007 Nov 7.
• [2] 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.
• [3] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.
• [9] 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.
• [10] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [11] 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.
• [12] Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres. Int J Mol Sci. 2020 Aug 3;21(15):5564. doi: 10.3390/ijms21155564.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.