Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4L2SSB)

• DOT Name: Gamma-aminobutyric acid receptor subunit beta-1 (GABRB1)
• Synonyms: GABA(A) receptor subunit beta-1
• Gene Name: GABRB1
• Related Disease:
  Acute coronary syndrome
  Autism
  Bipolar disorder
  Cervical carcinoma
  Developmental and epileptic encephalopathy, 45
  Fanconi anemia complementation group A
  Fanconi's anemia
  Friedreich ataxia 1
  Hepatic coma
  Hepatic encephalopathy
  Polycystic ovarian syndrome
  Schizophrenia
  Adult respiratory distress syndrome
  Alcohol dependence
• UniProt ID: GBRB1_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MWTVQNRESLGLLSFPVMITMVCCAHSTNEPSNMSYVKETVDRLLKGYDIRLRPDFGGPP
  VDVGMRIDVASIDMVSEVNMDYTLTMYFQQSWKDKRLSYSGIPLNLTLDNRVADQLWVPD
  TYFLNDKKSFVHGVTVKNRMIRLHPDGTVLYGLRITTTAACMMDLRRYPLDEQNCTLEIE
  SYGYTTDDIEFYWNGGEGAVTGVNKIELPQFSIVDYKMVSKKVEFTTGAYPRLSLSFRLK
  RNIGYFILQTYMPSTLITILSWVSFWINYDASAARVALGITTVLTMTTISTHLRETLPKI
  PYVKAIDIYLMGCFVFVFLALLEYAFVNYIFFGKGPQKKGASKQDQSANEKNKLEMNKVQ
  VDAHGNILLSTLEIRNETSGSEVLTSVSDPKATMYSYDSASIQYRKPLSSREAYGRALDR
  HGVPSKGRIRRRASQLKVKIPDLTDVNSIDKWSRMFFPITFSLFNVVYWLYYVH
• Function: Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as a receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as a ligand-gated chloride channel.
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[1]
Autism	DISV4V1Z	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Genetic Variation	[4]
Developmental and epileptic encephalopathy, 45	DISQQLYN	Strong	Autosomal dominant	[5]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Altered Expression	[2]
Fanconi's anemia	DISGW6Q8	Strong	Altered Expression	[2]
Friedreich ataxia 1	DIS285GE	Strong	Altered Expression	[2]
Hepatic coma	DISILSPO	Strong	Biomarker	[6]
Hepatic encephalopathy	DISEAKAN	Strong	Biomarker	[6]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[7]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[8]
Adult respiratory distress syndrome	DISIJV47	Limited	Biomarker	[9]
Alcohol dependence	DIS4ZSCO	Limited	Biomarker	[10]

6 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-1 (GABRB1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gamma-aminobutyric acid receptor subunit beta-1 (GABRB1).	[12]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Gamma-aminobutyric acid receptor subunit beta-1 (GABRB1).	[2]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Gamma-aminobutyric acid receptor subunit beta-1 (GABRB1).	[14]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Gamma-aminobutyric acid receptor subunit beta-1 (GABRB1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gamma-aminobutyric acid receptor subunit beta-1 (GABRB1).	[17]

1 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-1 (GABRB1).	[16]

2 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-1 (GABRB1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Gamma-aminobutyric acid receptor subunit beta-1 (GABRB1).	[19]

References

• [1] Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib.PLoS One. 2017 Jul 28;12(7):e0182115. doi: 10.1371/journal.pone.0182115. eCollection 2017.
• [2] The effect of folic acid on GABA(A)-B 1 receptor subunit. Adv Exp Med Biol. 2013;775:101-9. doi: 10.1007/978-1-4614-6130-2_8.
• [3] Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype.Mol Psychiatry. 2010 Feb;15(2):146-53. doi: 10.1038/mp.2008.66. Epub 2008 Jul 1.
• [4] Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study.PLoS Genet. 2017 Aug 14;13(8):e1006866. doi: 10.1371/journal.pgen.1006866. eCollection 2017 Aug.
• [5] Epileptic encephalopathy de novo GABRB mutations impair -aminobutyric acid type A receptor function. Ann Neurol. 2016 May;79(5):806-825. doi: 10.1002/ana.24631.
• [6] Expression of gamma-aminobutyric acid A receptor subunits alpha1, beta1, gamma2 mRNA in rats with hepatic encephalopathy.World J Gastroenterol. 2005 Jun 7;11(21):3319-22. doi: 10.3748/wjg.v11.i21.3319.
• [7] High Genetic Risk Scores of ASIC2, MACROD2, CHRM3, and C2orf83 Genetic Variants Associated with Polycystic Ovary Syndrome Impair Insulin Sensitivity and Interact with Energy Intake in Korean Women.Gynecol Obstet Invest. 2019;84(3):225-236. doi: 10.1159/000493131. Epub 2018 Oct 19.
• [8] Protein-interaction-network-based analysis for genome-wide association analysis of schizophrenia in Han Chinese population.J Psychiatr Res. 2014 Mar;50:73-8. doi: 10.1016/j.jpsychires.2013.11.014. Epub 2013 Dec 13.
• [9] MicroRNA and mRNA expression profiling in rat acute respiratory distress syndrome.BMC Med Genomics. 2014 Jul 28;7:46. doi: 10.1186/1755-8794-7-46.
• [10] GABA(A) receptor beta isoform protein expression in human alcoholic brain: interaction with genotype.Neurochem Int. 2006 Nov;49(6):557-67. doi: 10.1016/j.neuint.2006.04.008.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] The effect of folic acid on GABA(A)-B 1 receptor subunit. Adv Exp Med Biol. 2013;775:101-9. doi: 10.1007/978-1-4614-6130-2_8.
• [14] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [15] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.