Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT80C3D4)

• DOT Name: Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3)
• Synonyms: GABA(A) receptor subunit beta-3
• Gene Name: GABRB3
• Related Disease:
  Alcohol use disorder
  Attention deficit hyperactivity disorder
  Developmental and epileptic encephalopathy, 43
  Epilepsy syndrome
  Epilepsy, childhood absence, susceptibility to, 5
  Infantile spasm
  Angelman syndrome
  Autism spectrum disorder
  Bipolar disorder
  Chromosomal disorder
  Epilepsy
  Epilepsy, idiopathic generalized
  Hepatocellular carcinoma
  Heroin dependence
  Hypopigmentation of the skin
  Intellectual disability
  Isolated cleft lip
  Juvenile myoclonic epilepsy
  Neurodevelopmental disorder
  Pancreatic tumour
  Panic disorder
  Schizophrenia
  Substance abuse
  Temporal lobe epilepsy
  West syndrome
  Cleft lip/palate
  Dravet syndrome
  Movement disorder
  Absence seizure
  LennoxGastaut syndrome
  Alcohol dependence
  Cleft palate
  Depression
  Insomnia
  Isolated cleft palate
  Neuroblastoma
  Pervasive developmental disorder
  Post-traumatic stress disorder
  Prader-Willi syndrome
  Rett syndrome
  Sleep disorder, initiating and maintaining sleep
• UniProt ID: GBRB3_HUMAN
• PDB ID: 4COF; 5O8F; 5OJM; 6A96; 6HUG; 6HUJ; 6HUK; 6HUO; 6HUP; 6I53; 6QFA; 7PBD; 7PBZ; 7PC0; 7QN5; 7QN6; 7QN7; 7QN8; 7QN9; 7QNA; 7QNB; 7QNC; 7QND; 7QNE; 8PVB
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MWGLAGGRLFGIFSAPVLVAVVCCAQSVNDPGNMSFVKETVDKLLKGYDIRLRPDFGGPP
  VCVGMNIDIASIDMVSEVNMDYTLTMYFQQYWRDKRLAYSGIPLNLTLDNRVADQLWVPD
  TYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDLRRYPLDEQNCTLEIE
  SYGYTTDDIEFYWRGGDKAVTGVERIELPQFSIVEHRLVSRNVVFATGAYPRLSLSFRLK
  RNIGYFILQTYMPSILITILSWVSFWINYDASAARVALGITTVLTMTTINTHLRETLPKI
  PYVKAIDMYLMGCFVFVFLALLEYAFVNYIFFGRGPQRQKKLAEKTAKAKNDRSKSESNR
  VDAHGNILLTSLEVHNEMNEVSGGIGDTRNSAISFDNSGIQYRKQSMPREGHGRFLGDRS
  LPHKKTHLRRRSSQLKIKIPDLTDVNAIDRWSRIVFPFTFSLFNLVYWLYYVN
• 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/beta3/gamma2 receptor exhibits synaptogenic activity. The alpha2/beta3/gamma2 receptor shows very little or no synaptogenic activity. Functions also as histamine receptor and mediates cellular responses to histamine. Plays an important role in somatosensation and in the production of antinociception.
• 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

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol use disorder	DISMB65Y	Definitive	Genetic Variation	[1]
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Genetic Variation	[2]
Developmental and epileptic encephalopathy, 43	DISPGDAA	Definitive	Autosomal dominant	[3]
Epilepsy syndrome	DISLYXJ3	Definitive	Genetic Variation	[4]
Epilepsy, childhood absence, susceptibility to, 5	DIS1AU30	Definitive	Autosomal dominant	[5]
Infantile spasm	DISZSKDG	Definitive	Autosomal dominant	[6]
Angelman syndrome	DIS4QVXO	Strong	Genetic Variation	[7]
Autism spectrum disorder	DISXK8NV	Strong	Altered Expression	[8]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[9]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[10]
Epilepsy	DISBB28L	Strong	Genetic Variation	[4]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
Heroin dependence	DISQ1H57	Strong	Genetic Variation	[13]
Hypopigmentation of the skin	DIS39YKC	Strong	Biomarker	[14]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[4]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[15]
Juvenile myoclonic epilepsy	DISYXV1N	Strong	Genetic Variation	[16]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[17]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[18]
Panic disorder	DISD3VNY	Strong	Biomarker	[19]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[20]
Substance abuse	DIS327VW	Strong	Biomarker	[13]
Temporal lobe epilepsy	DISNOPXX	Strong	Genetic Variation	[21]
West syndrome	DISLIAU9	Strong	Genetic Variation	[4]
Cleft lip/palate	DIS14IG3	moderate	Biomarker	[22]
Dravet syndrome	DISJF7LY	moderate	Biomarker	[23]
Movement disorder	DISOJJ2D	moderate	Genetic Variation	[24]
Absence seizure	DIS4709R	Supportive	Autosomal dominant	[25]
LennoxGastaut syndrome	DISOTGO5	Supportive	Autosomal dominant	[26]
Alcohol dependence	DIS4ZSCO	Limited	Biomarker	[27]
Cleft palate	DIS6G5TF	Limited	Genetic Variation	[28]
Depression	DIS3XJ69	Limited	Biomarker	[29]
Insomnia	DIS0AFR7	Limited	Biomarker	[30]
Isolated cleft palate	DISV80CD	Limited	Genetic Variation	[28]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[31]
Pervasive developmental disorder	DIS51975	Limited	Genetic Variation	[8]
Post-traumatic stress disorder	DISHL1EY	Limited	Genetic Variation	[32]
Prader-Willi syndrome	DISYWMLU	Limited	Biomarker	[14]
Rett syndrome	DISGG5UV	Limited	Biomarker	[33]
Sleep disorder, initiating and maintaining sleep	DISVOIRA	Limited	Biomarker	[30]

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-3 (GABRB3) increases the transport of Chloride.	[51]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
LORECLEZOLE	DMCZI62	Discontinued in Phase 2	Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3) affects the response to substance of LORECLEZOLE.	[52]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[37]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[38]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[39]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[40]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[41]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[42]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[44]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[40]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[42]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[48]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Lindane	DMB8CNL	Approved	Lindane affects the binding of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[43]
Flunitrazepam	DMGR5Z3	Approved	Flunitrazepam affects the binding of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[45]
Flumazenil	DMPCG2L	Approved	Flumazenil affects the binding of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[46]
TBPS	DMFC3XP	Investigative	TBPS affects the binding of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[50]
Muscimol	DMNTF2O	Investigative	Muscimol affects the binding of Gamma-aminobutyric acid receptor subunit beta-3 (GABRB3).	[45]

References

• [1] Polymorphisms of the dopamine D2 receptor, serotonin transporter, and GABA(A) receptor beta(3) subunit genes and alcoholism in Mexican-Americans.Alcohol. 2004 Jan;32(1):45-52. doi: 10.1016/j.alcohol.2003.11.002.
• [2] Association between GABA3 Gene Polymorphisms and Attention Deficit Hyperactivity Disorder in Korean Children.Psychiatry Investig. 2017 Sep;14(5):693-697. doi: 10.4306/pi.2017.14.5.693. Epub 2017 Sep 11.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Synaptic clustering differences due to different GABRB3 mutations cause variable epilepsy syndromes.Brain. 2019 Oct 1;142(10):3028-3044. doi: 10.1093/brain/awz250.
• [5] De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies. Am J Hum Genet. 2016 Aug 4;99(2):287-98. doi: 10.1016/j.ajhg.2016.06.003. Epub 2016 Jul 28.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes.Biol Psychiatry. 2019 May 1;85(9):752-759. doi: 10.1016/j.biopsych.2019.01.008. Epub 2019 Jan 19.
• [8] Meta-analysis of GABRB3 Gene Polymorphisms and Susceptibility to Autism Spectrum Disorder.J Mol Neurosci. 2018 Aug;65(4):432-437. doi: 10.1007/s12031-018-1114-2. Epub 2018 Jul 18.
• [9] Variation at the GABAA receptor gene, Rho 1 (GABRR1) associated with susceptibility to bipolar schizoaffective disorder.Am J Med Genet B Neuropsychiatr Genet. 2010 Oct 5;153B(7):1347-9. doi: 10.1002/ajmg.b.31108.
• [10] Autistic disorder and chromosome 15q11-q13: construction and analysis of a BAC/PAC contig.Genomics. 1999 Dec 15;62(3):325-31. doi: 10.1006/geno.1999.6017.
• [11] Screening of GABRB3 in French-Canadian families with idiopathic generalized epilepsy.Epilepsia. 2010 Sep;51(9):1894-7. doi: 10.1111/j.1528-1167.2010.02642.x.
• [12] Decreased hepatocyte membrane potential differences and GABAA-beta3 expression in human hepatocellular carcinoma.Hepatology. 2007 Mar;45(3):735-45. doi: 10.1002/hep.21562.
• [13] Association analysis of GABRB3 promoter variants with heroin dependence.PLoS One. 2014 Jul 15;9(7):e102227. doi: 10.1371/journal.pone.0102227. eCollection 2014.
• [14] Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation.Cell Rep. 2016 Dec 20;17(12):3115-3124. doi: 10.1016/j.celrep.2016.11.067.
• [15] Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate.Hum Genet. 2002 Jan;110(1):15-20. doi: 10.1007/s00439-001-0639-5. Epub 2001 Nov 10.
• [16] Seizures of idiopathic generalized epilepsies.Epilepsia. 2005;46 Suppl 9:34-47. doi: 10.1111/j.1528-1167.2005.00312.x.
• [17] De novo variants in neurodevelopmental disorders with epilepsy.Nat Genet. 2018 Jul;50(7):1048-1053. doi: 10.1038/s41588-018-0143-7. Epub 2018 Jun 25.
• [18] The gamma-aminobutyric acid A receptor pi subunit is overexpressed in pancreatic adenocarcinomas.JOP. 2005 Mar 10;6(2):136-42.
• [19] Evidence for linkage and association of GABRB3 and GABRA5 to panic disorder.Neuropsychopharmacology. 2014 Sep;39(10):2423-31. doi: 10.1038/npp.2014.92. Epub 2014 May 23.
• [20] Functional analysis of haplotypes and promoter activity at the 5' region of the human GABRB3 gene and associations with schizophrenia.Mol Genet Genomic Med. 2019 May;7(5):e652. doi: 10.1002/mgg3.652. Epub 2019 Mar 25.
• [21] Promoter variants determine -aminobutyric acid homeostasis-related gene transcription in human epileptic hippocampi.J Neuropathol Exp Neurol. 2011 Dec;70(12):1080-8. doi: 10.1097/NEN.0b013e318238b9af.
• [22] Patterns of some extracellular matrix gene expression are similar in cells from cleft lip-palate patients and in human palatal fibroblasts exposed to diazepam in culture. Toxicology. 2009 Mar 4;257(1-2):10-6. doi: 10.1016/j.tox.2008.12.002. Epub 2008 Dec 9.
• [23] A mutation in GABRB3 associated with Dravet syndrome.Am J Med Genet A. 2017 Aug;173(8):2126-2131. doi: 10.1002/ajmg.a.38282. Epub 2017 May 24.
• [24] Mutations in GABRB3: From febrile seizures to epileptic encephalopathies.Neurology. 2017 Jan 31;88(5):483-492. doi: 10.1212/WNL.0000000000003565. Epub 2017 Jan 4.
• [25] Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am J Hum Genet. 2008 Jun;82(6):1249-61. doi: 10.1016/j.ajhg.2008.04.020.
• [26] De novo mutations in epileptic encephalopathies. Nature. 2013 Sep 12;501(7466):217-21. doi: 10.1038/nature12439. Epub 2013 Aug 11.
• [27] Array-based profiling of DNA methylation changes associated with alcohol dependence.Alcohol Clin Exp Res. 2013 Jan;37 Suppl 1(Suppl 1):E108-15. doi: 10.1111/j.1530-0277.2012.01928.x. Epub 2012 Aug 24.
• [28] Cleft Palate as Distinguishing Feature in a Patient with GABRB3 Epileptic Encephalopathy.Neuropediatrics. 2019 Dec;50(6):378-381. doi: 10.1055/s-0039-1693143. Epub 2019 Jul 18.
• [29] Investigating association of four gene regions (GABRB3, MAOB, PAH, and SLC6A4) with five symptoms in schizophrenia.Psychiatry Res. 2012 Jul 30;198(2):202-6. doi: 10.1016/j.psychres.2011.12.035. Epub 2012 Mar 12.
• [30] Functional characterization of the new human GABA(A) receptor mutation beta3(R192H).Hum Genet. 2002 Aug;111(2):154-60. doi: 10.1007/s00439-002-0766-7. Epub 2002 Jul 16.
• [31] Minimal residual disease monitoring in neuroblastoma patients based on the expression of a set of real-time RT-PCR markers in tumor-initiating cells.Oncol Rep. 2013 Apr;29(4):1629-36. doi: 10.3892/or.2013.2286. Epub 2013 Feb 12.
• [32] GABA(A) receptor beta 3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population.Psychiatry Res. 2001 Nov 1;104(2):109-17. doi: 10.1016/s0165-1781(01)00296-7.
• [33] 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders.Hum Mol Genet. 2007 Mar 15;16(6):691-703. doi: 10.1093/hmg/ddm014. Epub 2007 Mar 5.
• [34] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [35] 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.
• [36] 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.
• [37] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [38] Gonadal steroids regulate GABAA receptor subunit mRNA expression in NT2-N neurons. Brain Res Mol Brain Res. 2005 Aug 18;138(2):105-15. doi: 10.1016/j.molbrainres.2004.10.047.
• [39] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [40] 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.
• [41] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [42] 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.
• [43] GABA receptor subunit composition relative to insecticide potency and selectivity. Toxicol Lett. 2001 Jul 6;122(3):215-22. doi: 10.1016/s0378-4274(01)00366-6.
• [44] Retinoic acid, GABA-ergic, and TGF-beta signaling systems are involved in human cleft palate fibroblast phenotype. Mol Med. 2006 Sep-Oct;12(9-10):237-45. doi: 10.2119/2006C00026.Baroni.
• [45] p-(4-Azipentyl)propofol: a potent photoreactive general anesthetic derivative of propofol. J Med Chem. 2011 Dec 8;54(23):8124-35. doi: 10.1021/jm200943f. Epub 2011 Nov 10.
• [46] Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors. Mol Pharmacol. 1996 Feb;49(2):253-9.
• [47] 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.
• [48] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [49] 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.
• [50] The interactions of hexachlorocyclohexane isomers with human gamma-aminobutyric acid(A) receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther. 1997 Sep;282(3):1557-64.
• [51] 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.
• [52] 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.