Details of Drug Off-Target (DOT)

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

• DOT Name: Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5)
• Synonyms: GABA(A) receptor subunit alpha-5
• Gene Name: GABRA5
• Related Disease:
  Developmental and epileptic encephalopathy, 79
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: GBRA5_HUMAN
• PDB ID: 5O8F; 5OJM; 6A96; 8BEJ; 8BGI; 8BHA; 8BHB; 8BHG; 8BHI; 8BHK; 8BHM; 8BHO; 8BHQ; 8BHR; 8BHS
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MDNGMFSGFIMIKNLLLFCISMNLSSHFGFSQMPTSSVKDETNDNITIFTRILDGLLDGY
  DNRLRPGLGERITQVRTDIYVTSFGPVSDTEMEYTIDVFFRQSWKDERLRFKGPMQRLPL
  NNLLASKIWTPDTFFHNGKKSIAHNMTTPNKLLRLEDDGTLLYTMRLTISAECPMQLEDF
  PMDAHACPLKFGSYAYPNSEVVYVWTNGSTKSVVVAEDGSRLNQYHLMGQTVGTENISTS
  TGEYTIMTAHFHLKRKIGYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTM
  TTLSISARNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGWAWDGKKALEAA
  KIKKKREVILNKSTNAFTTGKMSHPPNIPKEQTPAGTSNTTSVSVKPSEEKTSESKKTYN
  SISKIDKMSRIVFPVLFGTFNLVYWATYLNREPVIKGAASPK
• Function: Ligand-gated chloride channel subunit which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain. May be involved in GABA-A receptor assembly, and GABA-A receptor immobilization and accumulation by gephyrin at the synapse.
• 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, 79	DIS10IB8	Strong	Autosomal dominant	[1]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[2]

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-5 (GABRA5).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Gamma-aminobutyric acid receptor subunit alpha-5 (GABRA5).	[14]

References

• [1] Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population. PLoS One. 2016 Sep 13;11(9):e0162883. doi: 10.1371/journal.pone.0162883. eCollection 2016.
• [2] Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies. Brain. 2019 Jul 1;142(7):1938-1954. doi: 10.1093/brain/awz123.
• [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] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] 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.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] 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.
• [12] 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.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.