Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC8C2NC)

• DOT Name: Glycine receptor subunit alpha-3 (GLRA3)
• Gene Name: GLRA3
• Related Disease:
  Epilepsy
  Autism
  Epithelial ovarian cancer
  Intellectual disability
  Major depressive disorder
  Malignant neoplasm
  Metastatic prostate carcinoma
  Obesity
  Type-1 diabetes
  Rett syndrome
  Temporal lobe epilepsy
• UniProt ID: GLRA3_HUMAN
• PDB ID: 5CFB; 5TIN; 5TIO; 5VDH; 5VDI
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MAHVRHFRTLVSGFYFWEAALLLSLVATKETDSARSRSAPMSPSDFLDKLMGRTSGYDAR
  IRPNFKGPPVNVTCNIFINSFGSIAETTMDYRVNIFLRQKWNDPRLAYSEYPDDSLDLDP
  SMLDSIWKPDLFFANEKGANFHEVTTDNKLLRIFKNGNVLYSIRLTLTLSCPMDLKNFPM
  DVQTCIMQLESFGYTMNDLIFEWQDEAPVQVAEGLTLPQFLLKEEKDLRYCTKHYNTGKF
  TCIEVRFHLERQMGYYLIQMYIPSLLIVILSWVSFWINMDAAPARVALGITTVLTMTTQS
  SGSRASLPKVSYVKAIDIWMAVCLLFVFSALLEYAAVNFVSRQHKELLRFRRKRKNKTEA
  FALEKFYRFSDMDDEVRESRFSFTAYGMGPCLQAKDGMTPKGPNHPVQVMPKSPDEMRKV
  FIDRAKKIDTISRACFPLAFLIFNIFYWVIYKILRHEDIHQQQD
• Function: Glycine receptors are ligand-gated chloride channels. Channel opening is triggered by extracellular glycine. Channel characteristics depend on the subunit composition; heteropentameric channels display faster channel closure. Plays an important role in the down-regulation of neuronal excitability. Contributes to the generation of inhibitory postsynaptic currents. Contributes to increased pain perception in response to increased prostaglandin E2 levels. Plays a role in cellular responses to ethanol.
• Tissue Specificity: Widely distributed throughout the central nervous system.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: Neurotransmitter receptors and postsynaptic signal transmission (R-HSA-112314)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[1]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[4]
Malignant neoplasm	DISS6SNG	Strong	Genetic Variation	[5]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Genetic Variation	[5]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[7]
Rett syndrome	DISGG5UV	Limited	Biomarker	[8]
Temporal lobe epilepsy	DISNOPXX	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Glycine receptor subunit alpha-3 (GLRA3).	[10]
Lindane	DMB8CNL	Approved	Lindane decreases the activity of Glycine receptor subunit alpha-3 (GLRA3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glycine receptor subunit alpha-3 (GLRA3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Glycine receptor subunit alpha-3 (GLRA3).	[13]

References

• [1] Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.Am J Hum Genet. 2016 Dec 1;99(6):1261-1280. doi: 10.1016/j.ajhg.2016.10.002. Epub 2016 Nov 10.
• [2] A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R.BMC Med Genet. 2004 Apr 16;5:10. doi: 10.1186/1471-2350-5-10.
• [3] In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer.Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7301-E7310. doi: 10.1073/pnas.1705441114. Epub 2017 Aug 15.
• [4] P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder.Hum Mol Genet. 2006 Aug 15;15(16):2438-45. doi: 10.1093/hmg/ddl166. Epub 2006 Jul 5.
• [5] Genetic and clinical factors associated with obesity among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort.Cancer. 2015 Jul 1;121(13):2262-70. doi: 10.1002/cncr.29153. Epub 2015 May 11.
• [6] Transition from androgenic to neurosteroidal action of 5-androstane-3, 17-diol through the type A -aminobutyric acid receptor in prostate cancer progression.J Steroid Biochem Mol Biol. 2018 Apr;178:89-98. doi: 10.1016/j.jsbmb.2017.11.006. Epub 2017 Nov 21.
• [7] Confirmation of GLRA3 as a susceptibility locus for albuminuria in Finnish patients with type 1 diabetes.Sci Rep. 2018 Aug 17;8(1):12408. doi: 10.1038/s41598-018-29211-1.
• [8] Breathing disturbances in a model of Rett syndrome: A potential involvement of the glycine receptor 3 subunit?.Respir Physiol Neurobiol. 2018 Jan;248:43-47. doi: 10.1016/j.resp.2017.11.011. Epub 2017 Dec 5.
• [9] Splice-specific roles of glycine receptor alpha3 in the hippocampus.Eur J Neurosci. 2009 Sep;30(6):1077-91. doi: 10.1111/j.1460-9568.2009.06903.x. Epub 2009 Sep 1.
• [10] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [11] Mechanism of action of the insecticides, lindane and fipronil, on glycine receptor chloride channels. Br J Pharmacol. 2012 Apr;165(8):2707-20. doi: 10.1111/j.1476-5381.2011.01722.x.
• [12] 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.
• [13] 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.