Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9TZ2E0)

• DOT Name: Gamma-aminobutyric acid receptor subunit alpha-2 (GABRA2)
• Synonyms: GABA(A) receptor subunit alpha-2
• Gene Name: GABRA2
• Related Disease:
  Developmental and epileptic encephalopathy, 78
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: GBRA2_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MKTKLNIYNMQFLLFVFLVWDPARLVLANIQEDEAKNNITIFTRILDRLLDGYDNRLRPG
  LGDSITEVFTNIYVTSFGPVSDTDMEYTIDVFFRQKWKDERLKFKGPMNILRLNNLMASK
  IWTPDTFFHNGKKSVAHNMTMPNKLLRIQDDGTLLYTMRLTVQAECPMHLEDFPMDAHSC
  PLKFGSYAYTTSEVTYIWTYNASDSVQVAPDGSRLNQYDLLGQSIGKETIKSSTGEYTVM
  TAHFHLKRKIGYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTMTTLSISA
  RNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGWAWDGKSVVNDKKKEKASV
  MIQNNAYAVAVANYAPNLSKDPVLSTISKSATTPEPNKKPENKPAEAKKTFNSVSKIDRM
  SRIVFPVLFGTFNLVYWATYLNREPVLGVSP
• 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 alpha2/beta2/gamma2 receptor exhibits synaptogenic activity whereas the alpha2/beta3/gamma2 receptor shows very little or no synaptogenic activity.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 78	DISS8AXB	Strong	Autosomal dominant	[1]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Gamma-aminobutyric acid receptor subunit alpha-2 (GABRA2) affects the response to substance of Temozolomide.	[8]

2 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-2 (GABRA2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gamma-aminobutyric acid receptor subunit alpha-2 (GABRA2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Gamma-aminobutyric acid receptor subunit alpha-2 (GABRA2).	[4]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Gamma-aminobutyric acid receptor subunit alpha-2 (GABRA2).	[5]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Gamma-aminobutyric acid receptor subunit alpha-2 (GABRA2).	[6]

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] Novel GABRA2 variants in epileptic encephalopathy and intellectual disability with seizures. Brain. 2019 May 1;142(5):e15. doi: 10.1093/brain/awz079.
• [3] 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.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] 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.
• [6] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [7] 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.
• [8] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.