Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD88Q92)

• DOT Name: Metabotropic glutamate receptor 2 (GRM2)
• Synonyms: mGluR2
• Gene Name: GRM2
• UniProt ID: GRM2_HUMAN
• PDB ID: 4XAQ; 4XAS; 5CNI; 5CNJ; 5KZN; 5KZQ; 7E9G; 7EPA; 7EPB; 7EPD; 7MTQ; 7MTR; 7MTS; 8JCU; 8JCV; 8JCW; 8JCX; 8JCY; 8JCZ; 8JD0; 8JD1; 8JD2; 8JD3; 8JD4; 8JD5
• Pfam ID: PF00003 ; PF01094 ; PF07562
• Sequence:
  MGSLLALLALLLLWGAVAEGPAKKVLTLEGDLVLGGLFPVHQKGGPAEDCGPVNEHRGIQ
  RLEAMLFALDRINRDPHLLPGVRLGAHILDSCSKDTHALEQALDFVRASLSRGADGSRHI
  CPDGSYATHGDAPTAITGVIGGSYSDVSIQVANLLRLFQIPQISYASTSAKLSDKSRYDY
  FARTVPPDFFQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFELEARARNICVATSEK
  VGRAMSRAAFEGVVRALLQKPSARVAVLFTRSEDARELLAASQRLNASFTWVASDGWGAL
  ESVVAGSEGAAEGAITIELASYPISDFASYFQSLDPWNNSRNPWFREFWEQRFRCSFRQR
  DCAAHSLRAVPFEQESKIMFVVNAVYAMAHALHNMHRALCPNTTRLCDAMRPVNGRRLYK
  DFVLNVKFDAPFRPADTHNEVRFDRFGDGIGRYNIFTYLRAGSGRYRYQKVGYWAEGLTL
  DTSLIPWASPSAGPLPASRCSEPCLQNEVKSVQPGEVCCWLCIPCQPYEYRLDEFTCADC
  GLGYWPNASLTGCFELPQEYIRWGDAWAVGPVTIACLGALATLFVLGVFVRHNATPVVKA
  SGRELCYILLGGVFLCYCMTFIFIAKPSTAVCTLRRLGLGTAFSVCYSALLTKTNRIARI
  FGGAREGAQRPRFISPASQVAICLALISGQLLIVVAWLVVEAPGTGKETAPERREVVTLR
  CNHRDASMLGSLAYNVLLIALCTLYAFKTRKCPENFNEAKFIGFTMYTTCIIWLAFLPIF
  YVTSSDYRVQTTTMCVSVSLSGSVVLGCLFAPKLHIILFQPQKNVVSHRAPTSRFGSAAA
  RASSSLGQGSGSQFVPTVCNGREVVDSTTSSL
• Function: G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization.
• Tissue Specificity: Detected in brain cortex (at protein level). Widely expressed in different regions of the adult brain as well as in fetal brain.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Neuroactive ligand-receptor interaction (hsa04080)
  Glutamatergic sy.pse (hsa04724)
  Cocaine addiction (hsa05030)
• Reactome Pathway:
  Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499)
  G alpha (i) signalling events (R-HSA-418594)

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
Methamphetamine	DMPM4SK	Approved	Metabotropic glutamate receptor 2 (GRM2) increases the response to substance of Methamphetamine.	[9]

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 Metabotropic glutamate receptor 2 (GRM2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Metabotropic glutamate receptor 2 (GRM2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Metabotropic glutamate receptor 2 (GRM2).	[2]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Metabotropic glutamate receptor 2 (GRM2).	[3]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Metabotropic glutamate receptor 2 (GRM2).	[4]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Metabotropic glutamate receptor 2 (GRM2).	[5]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Metabotropic glutamate receptor 2 (GRM2).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Metabotropic glutamate receptor 2 (GRM2).	[8]

References

• [1] 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.
• [2] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] 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.
• [5] 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.
• [6] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [7] 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.
• [8] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [9] Association analysis of GRM2 and HTR2A with methamphetamine-induced psychosis and schizophrenia in the Japanese population. Prog Neuropsychopharmacol Biol Psychiatry. 2010 May 30;34(4):639-44. doi: 10.1016/j.pnpbp.2010.03.002. Epub 2010 Mar 6.