Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX4UC3O)

• DOT Name: Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)
• Synonyms: GABA(A) receptor subunit alpha-6
• Gene Name: GABRA6
• Related Disease:
  Epilepsy
  Adrenal gland hyperfunction
  Bipolar I disorder
  Depression
  Epilepsy, idiopathic generalized
  Gastroesophageal reflux disease
  Major depressive disorder
  Obesity
  Panic disorder
  Mood disorder
  Schizophrenia
  Absence epilepsy
  Absence seizure
• UniProt ID: GBRA6_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MASSLPWLCIILWLENALGKLEVEGNFYSENVSRILDNLLEGYDNRLRPGFGGAVTEVKT
  DIYVTSFGPVSDVEMEYTMDVFFRQTWTDERLKFGGPTEILSLNNLMVSKIWTPDTFFRN
  GKKSIAHNMTTPNKLFRIMQNGTILYTMRLTINADCPMRLVNFPMDGHACPLKFGSYAYP
  KSEIIYTWKKGPLYSVEVPEESSSLLQYDLIGQTVSSETIKSNTGEYVIMTVYFHLQRKM
  GYFMIQIYTPCIMTVILSQVSFWINKESVPARTVFGITTVLTMTTLSISARHSLPKVSYA
  TAMDWFIAVCFAFVFSALIEFAAVNYFTNLQTQKAKRKAQFAAPPTVTISKATEPLEAEI
  VLHPDSKYHLKKRITSLSLPIVSSSEANKVLTRAPILQSTPVTPPPLSPAFGGTSKIDQY
  SRILFPVAFAGFNLVYWVVYLSKDTMEVSSSVE
• 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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Adrenal gland hyperfunction	DISPP4ZK	Strong	Genetic Variation	[2]
Bipolar I disorder	DISD09EH	Strong	Genetic Variation	[3]
Depression	DIS3XJ69	Strong	Genetic Variation	[4]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Genetic Variation	[5]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Genetic Variation	[6]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Obesity	DIS47Y1K	Strong	Biomarker	[2]
Panic disorder	DISD3VNY	Strong	Genetic Variation	[7]
Mood disorder	DISLVMWO	moderate	Biomarker	[8]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[9]
Absence epilepsy	DISJPOUD	Limited	Genetic Variation	[10]
Absence seizure	DIS4709R	Limited	Genetic Variation	[10]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Midazolam	DMXOELT	Approved	Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6) decreases the response to substance of Midazolam.	[16]
Naltrexone	DMUL45H	Approved	Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6) affects the response to substance of Naltrexone.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6).	[12]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Flumazenil	DMPCG2L	Approved	Flumazenil affects the binding of Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6).	[14]

References

• [1] GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures.Pharmacogenet Genomics. 2013 Nov;23(11):605-10. doi: 10.1097/FPC.0000000000000000.
• [2] Association between a variant at the GABA(A)alpha6 receptor subunit gene, abdominal obesity, and cortisol secretion.Ann N Y Acad Sci. 2002 Jun;967:566-70. doi: 10.1111/j.1749-6632.2002.tb04318.x.
• [3] Contribution of genes in the GABAergic pathway to bipolar disorder and its executive function deficit in the Chinese Han population.Am J Med Genet B Neuropsychiatr Genet. 2018 Jan;177(1):50-67. doi: 10.1002/ajmg.b.32601. Epub 2017 Nov 14.
• [4] A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene.Sci Rep. 2017 Oct 10;7(1):12887. doi: 10.1038/s41598-017-12776-8.
• [5] Association of GABRA6 1519 T>C (rs3219151) and Synapsin II (rs37733634) gene polymorphisms with the development of idiopathic generalized epilepsy.Epilepsy Res. 2014 Oct;108(8):1267-73. doi: 10.1016/j.eplepsyres.2014.07.001. Epub 2014 Jul 18.
• [6] GABRA6 genetic polymorphism is associated with the risk of functional heartburn in Chinese.J Gastroenterol Hepatol. 2007 Feb;22(2):227-33. doi: 10.1111/j.1440-1746.2006.04441.x.
• [7] Association of TMEM132D, COMT, and GABRA6 genotypes with cingulate, frontal cortex and hippocampal emotional processing in panic and major depressive disorder.Int J Psychiatry Clin Pract. 2015;19(3):192-200. doi: 10.3109/13651501.2015.1043133. Epub 2015 May 14.
• [8] Evidence of association between gamma-aminobutyric acid type A receptor genes located on 5q34 and female patients with mood disorders.Neurosci Lett. 2003 Sep 25;349(1):9-12. doi: 10.1016/s0304-3940(03)00611-6.
• [9] Polymorphisms in microRNA target sites influence susceptibility to schizophrenia by altering the binding of miRNAs to their targets.Eur Neuropsychopharmacol. 2013 Oct;23(10):1182-9. doi: 10.1016/j.euroneuro.2012.12.002. Epub 2013 Jan 16.
• [10] The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 622 and 62 GABA(A) receptor channel gating and expression.J Physiol. 2011 Dec 1;589(Pt 23):5857-78. doi: 10.1113/jphysiol.2011.218883. Epub 2011 Sep 19.
• [11] 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.
• [12] 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.
• [13] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [14] Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors. Mol Pharmacol. 1996 Feb;49(2):253-9.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] GABA alpha6 receptors mediate midazolam-induced anxiolysis. J Clin Anesth. 2002 May;14(3):206-9. doi: 10.1016/s0952-8180(02)00343-4.
• [17] Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators. Addict Biol. 2009 Jul;14(3):328-37.