Details of Drug Off-Target (DOT)

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

• DOT Name: Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2)
• Synonyms: GABA(A) receptor subunit beta-2
• Gene Name: GABRB2
• Related Disease:
  Epileptic encephalopathy, infantile or early childhood, 2
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: GBRB2_HUMAN
• PDB ID: 6D6T; 6D6U; 6X3S; 6X3T; 6X3U; 6X3V; 6X3W; 6X3X; 6X3Z; 6X40; 7T0W; 7T0Z; 8DD2; 8DD3; 8SGO; 8SI9; 8SID
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MWRVRKRGYFGIWSFPLIIAAVCAQSVNDPSNMSLVKETVDRLLKGYDIRLRPDFGGPPV
  AVGMNIDIASIDMVSEVNMDYTLTMYFQQAWRDKRLSYNVIPLNLTLDNRVADQLWVPDT
  YFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDLRRYPLDEQNCTLEIES
  YGYTTDDIEFYWRGDDNAVTGVTKIELPQFSIVDYKLITKKVVFSTGSYPRLSLSFKLKR
  NIGYFILQTYMPSILITILSWVSFWINYDASAARVALGITTVLTMTTINTHLRETLPKIP
  YVKAIDMYLMGCFVFVFMALLEYALVNYIFFGRGPQRQKKAAEKAASANNEKMRLDVNKI
  FYKDIKQNGTQYRSLWDPTGNLSPTRRTTNYDFSLYTMDPHENILLSTLEIKNEMATSEA
  VMGLGDPRSTMLAYDASSIQYRKAGLPRHSFGRNALERHVAQKKSRLRRRASQLKITIPD
  LTDVNAIDRWSRIFFPVVFSFFNIVYWLYYVN
• Function: Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain. Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel. The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer. The alpha1/beta2/gamma2 receptor and the alpha2/beta2/gamma2 receptor exhibit synaptogenic activity. Functions also as histamine receptor and mediates cellular responses to histamine.
• Tissue Specificity: Isoform 1 and isoform 2 show reduced expression in schizophrenic brain. Isoform 3 shows increased expression in schizophrenic and bipolar disorder brains while isoform 4 shows reduced expression.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Morphine addiction (hsa05032)
  Nicotine addiction (hsa05033)
• Reactome Pathway:
  GABA receptor activation (R-HSA-977443)
  Signaling by ERBB4 (R-HSA-1236394)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epileptic encephalopathy, infantile or early childhood, 2	DIS20XB0	Definitive	Autosomal dominant	[1]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Naltrexone	DMUL45H	Approved	Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2) affects the response to substance of Naltrexone.	[13]
(+)-JQ1	DM1CZSJ	Phase 1	Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2) increases the response to substance of (+)-JQ1.	[15]
LORECLEZOLE	DMCZI62	Discontinued in Phase 2	Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2) affects the response to substance of LORECLEZOLE.	[16]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloride	DM1TJXA	Phase 3	Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2) increases the transport of Chloride.	[14]

9 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 Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[11]

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 increases the methylation of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[10]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
TBPS	DMFC3XP	Investigative	TBPS affects the binding of Gamma-aminobutyric acid receptor subunit beta-2 (GABRB2).	[12]

References

• [1] A novel variant in GABRB2 associated with intellectual disability and epilepsy. Am J Med Genet A. 2014 Nov;164A(11):2914-21. doi: 10.1002/ajmg.a.36714. Epub 2014 Aug 13.
• [2] High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Am J Hum Genet. 2017 Nov 2;101(5):664-685. doi: 10.1016/j.ajhg.2017.09.008.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] [3H]Ethynylbicycloorthobenzoate ([3H]EBOB) binding in recombinant GABAA receptors. Neurotoxicology. 2003 Dec;24(6):817-24. doi: 10.1016/S0161-813X(03)00051-2.
• [13] Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators. Addict Biol. 2009 Jul;14(3):328-37.
• [14] A novel allosteric modulatory site on the GABAA receptor beta subunit. Neuron. 1994 Apr;12(4):775-82. doi: 10.1016/0896-6273(94)90330-1.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] Heterogeneity of GABA(A) receptor-mediated responses in the human IMR-32 neuroblastoma cell line. J Neurosci Res. 2000 May 15;60(4):504-10. doi: 10.1002/(SICI)1097-4547(20000515)60:4<504::AID-JNR9>3.0.CO;2-Y.