Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC2W96H)

• DOT Name: Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1)
• Synonyms: GABA(A) receptor subunit alpha-1
• Gene Name: GABRA1
• Related Disease:
  Developmental and epileptic encephalopathy, 19
  Infantile spasm
  Epilepsy, idiopathic generalized, susceptibility to, 13
  Juvenile myoclonic epilepsy
  Obsolete Dravet syndrome
• UniProt ID: GBRA1_HUMAN
• PDB ID: 6CDU; 6D1S; 6D6T; 6D6U; 6HUG; 6HUJ; 6HUK; 6HUO; 6HUP; 6I53; 6X3S; 6X3T; 6X3U; 6X3V; 6X3W; 6X3X; 6X3Z; 6X40; 7PBD; 7PBZ; 7PC0; 7QNE; 7T0W; 7T0Z; 8DD2; 8DD3; 8SGO; 8SI9; 8SID
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MRKSPGLSDCLWAWILLLSTLTGRSYGQPSLQDELKDNTTVFTRILDRLLDGYDNRLRPG
  LGERVTEVKTDIFVTSFGPVSDHDMEYTIDVFFRQSWKDERLKFKGPMTVLRLNNLMASK
  IWTPDTFFHNGKKSVAHNMTMPNKLLRITEDGTLLYTMRLTVRAECPMHLEDFPMDAHAC
  PLKFGSYAYTRAEVVYEWTREPARSVVVAEDGSRLNQYDLLGQTVDSGIVQSSTGEYVVM
  TTHFHLKRKIGYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTMTTLSISA
  RNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGYAWDGKSVVPEKPKKVKDP
  LIKKNNTYAPTATSYTPNLARGDPGLATIAKSATIEPKEVKPETKPPEPKKTFNSVSKID
  RLSRIAFPLLFGIFNLVYWATYLNREPQLKAPTPHQ
• 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 alpha1/beta3/gamma2 receptor exhibit synaptogenic activity. GABRA1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection. Functions also as histamine receptor and mediates cellular responses to histamine.
• 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)
  Signaling by ERBB4 (R-HSA-1236394)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 19	DISOF3OT	Definitive	Autosomal dominant	[1]
Infantile spasm	DISZSKDG	Definitive	Autosomal dominant	[2]
Epilepsy, idiopathic generalized, susceptibility to, 13	DISZA3EN	Strong	Autosomal dominant	[3]
Juvenile myoclonic epilepsy	DISYXV1N	Supportive	Autosomal dominant	[4]
Obsolete Dravet syndrome	DISM4LMK	Supportive	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
GSK683699	DMTW79H	Phase 2	Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1) increases the response to substance of GSK683699.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[8]
Diazepam	DM08E9O	Approved	Diazepam affects the activity of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Flunitrazepam	DMGR5Z3	Approved	Flunitrazepam affects the binding of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[10]
TBPS	DMFC3XP	Investigative	TBPS affects the binding of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[14]
Muscimol	DMNTF2O	Investigative	Muscimol affects the binding of Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1).	[10]

References

• [1] 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.
• [2] 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.
• [3] Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002 Jun;31(2):184-9. doi: 10.1038/ng885. Epub 2002 May 6.
• [4] The quest for juvenile myoclonic epilepsy genes. Epilepsy Behav. 2013 Jul;28 Suppl 1:S52-7. doi: 10.1016/j.yebeh.2012.06.033.
• [5] GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology. 2014 Apr 8;82(14):1245-53. doi: 10.1212/WNL.0000000000000291. Epub 2014 Mar 12.
• [6] 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.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon. Psychopharmacology (Berl). 2005 Jul;180(2):191-205. doi: 10.1007/s00213-005-2212-8. Epub 2005 Apr 28.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] [3H]Ethynylbicycloorthobenzoate ([3H]EBOB) binding in recombinant GABAA receptors. Neurotoxicology. 2003 Dec;24(6):817-24. doi: 10.1016/S0161-813X(03)00051-2.
• [15] Genetic essential tremor in gamma-aminobutyric acidA receptor alpha1 subunit knockout mice. J Clin Invest. 2005 Mar;115(3):774-9. doi: 10.1172/JCI23625.