Details of Drug Off-Target (DOT)

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

• DOT Name: Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2)
• Synonyms: GABA(A) receptor subunit gamma-2
• Gene Name: GABRG2
• Related Disease:
  Epilepsy
  Developmental and epileptic encephalopathy, 74
  Febrile seizures, familial, 8
  Childhood epilepsy with centrotemporal spikes
  Generalized epilepsy with febrile seizures plus
  Obsolete Dravet syndrome
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: GBRG2_HUMAN
• PDB ID: 6D6T; 6D6U; 6HUG; 6HUJ; 6HUK; 6HUO; 6HUP; 6I53; 6X3S; 6X3T; 6X3U; 6X3V; 6X3W; 6X3X; 6X3Z; 6X40; 7QNB; 7QNE; 7T0W; 7T0Z; 8DD2; 8DD3; 8SGO; 8SI9; 8SID
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MSSPNIWSTGSSVYSTPVFSQKMTVWILLLLSLYPGFTSQKSDDDYEDYASNKTWVLTPK
  VPEGDVTVILNNLLEGYDNKLRPDIGVKPTLIHTDMYVNSIGPVNAINMEYTIDIFFAQT
  WYDRRLKFNSTIKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRMLRIWNDGRVLY
  TLRLTIDAECQLQLHNFPMDEHSCPLEFSSYGYPREEIVYQWKRSSVEVGDTRSWRLYQF
  SFVGLRNTTEVVKTTSGDYVVMSVYFDLSRRMGYFTIQTYIPCTLIVVLSWVSFWINKDA
  VPARTSLGITTVLTMTTLSTIARKSLPKVSYVTAMDLFVSVCFIFVFSALVEYGTLHYFV
  SNRKPSKDKDKKKKNPLLRMFSFKAPTIDIRPRSATIQMNNATHLQERDEEYGYECLDGK
  DCASFFCCFEDCRTGAWRHGRIHIRIAKMDSYARIFFPTAFCLFNLVYWVSYLYL
• 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. The alpha2/beta2/gamma2 receptor exhibits synatogenic activity whereas the alpha2/beta3/gamma2 receptor shows very little or no synaptogenic activity. 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)
  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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Autosomal dominant	[1]
Developmental and epileptic encephalopathy, 74	DISVNVOO	Strong	Autosomal dominant	[2]
Febrile seizures, familial, 8	DISA9SHW	Strong	Autosomal dominant	[3]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Supportive	Autosomal dominant	[4]
Generalized epilepsy with febrile seizures plus	DISJE0UU	Supportive	Autosomal dominant	[5]
Obsolete Dravet syndrome	DISM4LMK	Supportive	Autosomal dominant	[6]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2) increases the response to substance of Methamphetamine.	[16]
Diazepam	DM08E9O	Approved	Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2) affects the response to substance of Diazepam.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2).	[13]
Manganese	DMKT129	Investigative	Manganese increases the expression of Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2).	[14]

4 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 gamma-2 (GABRG2).	[9]
Flumazenil	DMPCG2L	Approved	Flumazenil affects the binding of Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2).	[10]
TBPS	DMFC3XP	Investigative	TBPS affects the binding of Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2).	[15]
Muscimol	DMNTF2O	Investigative	Muscimol affects the binding of Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2).	[12]

References

• [1] 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.
• [2] De novo GABRG2 mutations associated with epileptic encephalopathies. Brain. 2017 Jan;140(1):49-67. doi: 10.1093/brain/aww272. Epub 2016 Nov 17.
• [3] Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001 May;28(1):49-52. doi: 10.1038/ng0501-49.
• [4] Rare variants in -aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes. Ann Neurol. 2015 Jun;77(6):972-86. doi: 10.1002/ana.24395. Epub 2015 Mar 28.
• [5] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [6] Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet. 2002 Feb;70(2):530-6. doi: 10.1086/338710. Epub 2001 Dec 17.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [9] 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.
• [10] 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.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [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] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [15] [3H]Ethynylbicycloorthobenzoate ([3H]EBOB) binding in recombinant GABAA receptors. Neurotoxicology. 2003 Dec;24(6):817-24. doi: 10.1016/S0161-813X(03)00051-2.
• [16] Haplotype association between GABAA receptor gamma2 subunit gene (GABRG2) and methamphetamine use disorder. Pharmacogenomics J. 2005;5(2):89-95. doi: 10.1038/sj.tpj.6500292.
• [17] Heterogeneity of GABA(A) receptor-mediated responses in the human IMR-32 neuroblastoma cell line. J Neurosci Res. 2000 May 15;60(4):504-10. doi: 10.1002/(SICI)1097-4547(20000515)60:4<504::AID-JNR9>3.0.CO;2-Y.