Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF37UG4)

• DOT Name: Glycine receptor subunit beta (GLRB)
• Synonyms: Glycine receptor 58 kDa subunit
• Gene Name: GLRB
• Related Disease:
  Hyperekplexia 2
  Autism
  Epilepsy
  Panic disorder
  Intellectual disability
  Hereditary hyperekplexia
• UniProt ID: GLRB_HUMAN
• PDB ID: 5BKF; 5BKG; 7KUY; 7L31; 8DN2; 8DN3; 8DN4; 8DN5
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MKFLLTTAFLILISLWVEEAYSKEKSSKKGKGKKKQYLCPSQQSAEDLARVPANSTSNIL
  NRLLVSYDPRIRPNFKGIPVDVVVNIFINSFGSIQETTMDYRVNIFLRQKWNDPRLKLPS
  DFRGSDALTVDPTMYKCLWKPDLFFANEKSANFHDVTQENILLFIFRDGDVLVSMRLSIT
  LSCPLDLTLFPMDTQRCKMQLESFGYTTDDLRFIWQSGDPVQLEKIALPQFDIKKEDIEY
  GNCTKYYKGTGYYTCVEVIFTLRRQVGFYMMGVYAPTLLIVVLSWLSFWINPDASAARVP
  LGIFSVLSLASECTTLAAELPKVSYVKALDVWLIACLLFGFASLVEYAVVQVMLNNPKRV
  EAEKARIAKAEQADGKGGNVAKKNTVNGTGTPVHISTLQVGETRCKKVCTSKSDLRSNDF
  SIVGSLPRDFELSNYDCYGKPIEVNNGLGKSQAKNNKKPPPAKPVIPTAAKRIDLYARAL
  FPFCFLFFNVIYWSIYL
• Function: Glycine receptors are ligand-gated chloride channels. GLRB does not form ligand-gated ion channels by itself, but is part of heteromeric ligand-gated chloride channels. Channel opening is triggered by extracellular glycine. Heteropentameric channels composed of GLRB and GLRA1 are activated by lower glycine levels than homopentameric GLRA1. Plays an important role in the down-regulation of neuronal excitability. Contributes to the generation of inhibitory postsynaptic currents.
• 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperekplexia 2	DISJ9283	Definitive	Autosomal recessive	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Panic disorder	DISD3VNY	Strong	Genetic Variation	[4]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[5]
Hereditary hyperekplexia	DIS9YXFE	Supportive	Autosomal dominant	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Glycine receptor subunit beta (GLRB) affects the response to substance of Temozolomide.	[19]
DTI-015	DMXZRW0	Approved	Glycine receptor subunit beta (GLRB) affects the response to substance of DTI-015.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Glycine receptor subunit beta (GLRB).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glycine receptor subunit beta (GLRB).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glycine receptor subunit beta (GLRB).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Glycine receptor subunit beta (GLRB).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Glycine receptor subunit beta (GLRB).	[11]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Glycine receptor subunit beta (GLRB).	[12]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Glycine receptor subunit beta (GLRB).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Glycine receptor subunit beta (GLRB).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Glycine receptor subunit beta (GLRB).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glycine receptor subunit beta (GLRB).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glycine receptor subunit beta (GLRB).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glycine receptor subunit beta (GLRB).	[15]

References

• [1] Abnormal neurodevelopment outcome in case of neonatal hyperekplexia secondary to missense mutation in GLRB gene. BMJ Case Rep. 2020 Dec 15;13(12):e236152. doi: 10.1136/bcr-2020-236152.
• [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] Inhibition of miR-203 Reduces Spontaneous Recurrent Seizures in Mice.Mol Neurobiol. 2017 Jul;54(5):3300-3308. doi: 10.1007/s12035-016-9901-7. Epub 2016 May 10.
• [4] GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.Mol Psychiatry. 2017 Oct;22(10):1431-1439. doi: 10.1038/mp.2017.2. Epub 2017 Feb 7.
• [5] Partial deletion of GLRB and GRIA2 in a patient with intellectual disability. Eur J Hum Genet. 2013 Jan;21(1):112-4. doi: 10.1038/ejhg.2012.97. Epub 2012 Jun 6.
• [6] Hereditary Hyperekplexia Overview. 2007 Jul 31 [updated 2019 Dec 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [13] Ouabain at pathological concentrations might induce damage in human vascular endothelial cells. Acta Pharmacol Sin. 2006 Feb;27(2):165-72. doi: 10.1111/j.1745-7254.2006.00244.x.
• [14] 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.
• [15] 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.
• [16] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [17] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [18] 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.
• [19] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.