Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ3R10R)

• DOT Name: Glutamate receptor ionotropic, delta-2 (GRID2)
• Synonyms: GluD2; GluR delta-2 subunit
• Gene Name: GRID2
• Related Disease:
  Autism
  Autosomal recessive spinocerebellar ataxia 18
  Breast cancer
  Cerebellar disorder
  Inherited retinal dystrophy
  Mevalonate kinase deficiency
  Cerebellar ataxia
• UniProt ID: GRID2_HUMAN
• PDB ID: 5KC8; 5KCA
• Pfam ID: PF01094 ; PF00060 ; PF10613
• Sequence:
  MEVFPFLLVLSVWWSRTWDSANADSIIHIGAIFDESAKKDDEVFRTAVGDLNQNEEILQT
  EKITFSVTFVDGNNPFQAVQEACELMNQGILALVSSIGCTSAGSLQSLADAMHIPHLFIQ
  RSTAGTPRSGCGLTRSNRNDDYTLSVRPPVYLHDVILRVVTEYAWQKFIIFYDSEYDIRG
  IQEFLDKVSQQGMDVALQKVENNINKMITTLFDTMRIEELNRYRDTLRRAILVMNPATAK
  SFITEVVETNLVAFDCHWIIINEEINDVDVQELVRRSIGRLTIIRQTFPVPQNISQRCFR
  GNHRISSTLCDPKDPFAQNMEISNLYIYDTVLLLANAFHKKLEDRKWHSMASLSCIRKNS
  KPWQGGRSMLETIKKGGVSGLTGELEFGENGGNPNVHFEILGTNYGEELGRGVRKLGCWN
  PVTGLNGSLTDKKLENNMRGVVLRVVTVLEEPFVMVSENVLGKPKKYQGFSIDVLDALSN
  YLGFNYEIYVAPDHKYGSPQEDGTWNGLVGELVFKRADIGISALTITPDRENVVDFTTRY
  MDYSVGVLLRRAEKTVDMFACLAPFDLSLWACIAGTVLLVGLLVYLLNWLNPPRLQMGSM
  TSTTLYNSMWFVYGSFVQQGGEVPYTTLATRMMMGAWWLFALIVISSYTANLAAFLTITR
  IESSIQSLQDLSKQTEIPYGTVLDSAVYEHVRMKGLNPFERDSMYSQMWRMINRSNGSEN
  NVLESQAGIQKVKYGNYAFVWDAAVLEYVAINDPDCSFYTIGNTVADRGYGIALQHGSPY
  RDVFSQRILELQQNGDMDILKHKWWPKNGQCDLYSSVDTKQKGGALDIKSFAGVFCILAA
  GIVLSCFIAMLETWWNKRKGSRVPSKEDDKEIDLEHLHRRVNSLCTDDDSPHKQFSTSSI
  DLTPLDIDTLPTRQALEQISDFRNTHITTTTFIPEQIQTLSRTLSAKAASGFTFGNVPEH
  RTGPFRHRAPNGGFFRSPIKTMSSIPYQPTPTLGLNLGNDPDRGTSI
• 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. Promotes synaptogenesis and mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses through the beta-NRX1-CBLN1-GRID2 triad complex.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Long-term depression (hsa04730)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Biomarker	[1]
Autosomal recessive spinocerebellar ataxia 18	DIS7P7EV	Strong	Autosomal recessive	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Cerebellar disorder	DIS2O7WM	Strong	Biomarker	[4]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[5]
Mevalonate kinase deficiency	DISSTRVK	Strong	Biomarker	[6]
Cerebellar ataxia	DIS9IRAV	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Glutamate receptor ionotropic, delta-2 (GRID2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glutamate receptor ionotropic, delta-2 (GRID2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Glutamate receptor ionotropic, delta-2 (GRID2).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Glutamate receptor ionotropic, delta-2 (GRID2).	[9]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Glutamate receptor ionotropic, delta-2 (GRID2).	[10]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Glutamate receptor ionotropic, delta-2 (GRID2).	[11]

References

• [1] Potential of GRID2 receptor gene for preventing TNF-induced neurodegeneration in autism.Neurosci Lett. 2016 May 4;620:62-9. doi: 10.1016/j.neulet.2016.03.043. Epub 2016 Mar 25.
• [2] Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. Neurology. 2013 Oct 15;81(16):1378-86. doi: 10.1212/WNL.0b013e3182a841a3. Epub 2013 Sep 27.
• [3] A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.Nat Genet. 2010 Oct;42(10):885-92. doi: 10.1038/ng.669. Epub 2010 Sep 19.
• [4] Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features.BMC Med Genet. 2017 Dec 6;18(1):144. doi: 10.1186/s12881-017-0504-6.
• [5] Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion.Genet Med. 2015 Apr;17(4):291-9. doi: 10.1038/gim.2014.95. Epub 2014 Aug 14.
• [6] GRID2 a novel gene possibly associated with mevalonate kinase deficiency.Rheumatol Int. 2015 Apr;35(4):657-9. doi: 10.1007/s00296-014-3115-y. Epub 2014 Aug 22.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [11] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [12] 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.