Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5I7OI2)

• DOT Name: Gamma-aminobutyric acid receptor subunit alpha-4 (GABRA4)
• Synonyms: GABA(A) receptor subunit alpha-4
• Gene Name: GABRA4
• Related Disease:
  Autism
  Autism spectrum disorder
  Epilepsy
  Nicotine dependence
  Non-insulin dependent diabetes
  Pervasive developmental disorder
  Schizophrenia
  Sensory ataxia
  Status epilepticus seizure
  Essential tremor
• UniProt ID: GBRA4_HUMAN
• PDB ID: 7QN5; 7QN7; 7QN9; 7QNA; 7QNC
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MVSAKKVPAIALSAGVSFALLRFLCLAVCLNESPGQNQKEEKLCTENFTRILDSLLDGYD
  NRLRPGFGGPVTEVKTDIYVTSFGPVSDVEMEYTMDVFFRQTWIDKRLKYDGPIEILRLN
  NMMVTKVWTPDTFFRNGKKSVSHNMTAPNKLFRIMRNGTILYTMRLTISAECPMRLVDFP
  MDGHACPLKFGSYAYPKSEMIYTWTKGPEKSVEVPKESSSLVQYDLIGQTVSSETIKSIT
  GEYIVMTVYFHLRRKMGYFMIQTYIPCIMTVILSQVSFWINKESVPARTVFGITTVLTMT
  TLSISARHSLPKVSYATAMDWFIAVCFAFVFSALIEFAAVNYFTNIQMEKAKRKTSKPPQ
  EVPAAPVQREKHPEAPLQNTNANLNMRKRTNALVHSESDVGNRTEVGNHSSKSSTVVQES
  SKGTPRSYLASSPNPFSRANAAETISAARALPSASPTSIRTGYMPRKASVGSASTRHVFG
  SRLQRIKTTVNTIGATGKLSATPPPSAPPPSGSGTSKIDKYARILFPVTFGAFNMVYWVV
  YLSKDTMEKSESLM
• Function: GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Retrograde endocan.binoid sig.ling (hsa04723)
  GABAergic sy.pse (hsa04727)
  Taste transduction (hsa04742)
  Morphine addiction (hsa05032)
  Nicotine addiction (hsa05033)
• Reactome Pathway: GABA receptor activation (R-HSA-977443)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[2]
Epilepsy	DISBB28L	Strong	Biomarker	[3]
Nicotine dependence	DISZD9W7	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[5]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
Sensory ataxia	DISSMCYQ	Strong	Biomarker	[3]
Status epilepticus seizure	DISY3BIC	Strong	Altered Expression	[7]
Essential tremor	DIS7GBKQ	Disputed	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gamma-aminobutyric acid receptor subunit alpha-4 (GABRA4).	[9]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Gamma-aminobutyric acid receptor subunit alpha-4 (GABRA4).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Gamma-aminobutyric acid receptor subunit alpha-4 (GABRA4).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Gamma-aminobutyric acid receptor subunit alpha-4 (GABRA4).	[12]

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 Gamma-aminobutyric acid receptor subunit alpha-4 (GABRA4).	[13]

References

• [1] Association between GABA(A) receptor subunit polymorphisms and autism spectrum disorder (ASD).Psychiatry Res. 2015 Sep 30;229(1-2):580-2. doi: 10.1016/j.psychres.2015.07.077. Epub 2015 Jul 28.
• [2] Identification of rare noncoding sequence variants in gamma-aminobutyric acid A receptor, alpha 4 subunit in autism spectrum disorder.Neurogenetics. 2018 Jan;19(1):17-26. doi: 10.1007/s10048-017-0529-1. Epub 2017 Nov 18.
• [3] Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor alpha4 subunit expression.Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11894-9. doi: 10.1073/pnas.0501434102. Epub 2005 Aug 9.
• [4] Further evidence for an association between the gamma-aminobutyric acid receptor A, subunit 4 genes on chromosome 4 and Fagerstrm Test for Nicotine Dependence.Addiction. 2009 Mar;104(3):471-7. doi: 10.1111/j.1360-0443.2008.02445.x.
• [5] A genome-wide search for type 2 diabetes susceptibility genes in an extended Arab family.Ann Hum Genet. 2013 Nov;77(6):488-503. doi: 10.1111/ahg.12036. Epub 2013 Aug 13.
• [6] 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.
• [7] Enhancing GABA(A) receptor alpha 1 subunit levels in hippocampal dentate gyrus inhibits epilepsy development in an animal model of temporal lobe epilepsy.J Neurosci. 2006 Nov 1;26(44):11342-6. doi: 10.1523/JNEUROSCI.3329-06.2006.
• [8] Gamma-aminobutyric acid GABRA4, GABRE, and GABRQ receptor polymorphisms and risk for essential tremor.Pharmacogenet Genomics. 2011 Jul;21(7):436-9. doi: 10.1097/FPC.0b013e328345bec0.
• [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] 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.
• [11] 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.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] 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.