Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLCJJF3)

• DOT Name: Sodium- and chloride-dependent GABA transporter 1 (SLC6A1)
• Synonyms: GAT-1; Solute carrier family 6 member 1
• Gene Name: SLC6A1
• Related Disease:
  Myoclonic-atonic epilepsy
  Myoclonic-astatic epilepsy
• UniProt ID: SC6A1_HUMAN
• PDB ID: 7SK2; 7Y7V; 7Y7W; 7Y7Y; 7Y7Z
• Pfam ID: PF00209
• Sequence:
  MATNGSKVADGQISTEVSEAPVANDKPKTLVVKVQKKAADLPDRDTWKGRFDFLMSCVGY
  AIGLGNVWRFPYLCGKNGGGAFLIPYFLTLIFAGVPLFLLECSLGQYTSIGGLGVWKLAP
  MFKGVGLAAAVLSFWLNIYYIVIISWAIYYLYNSFTTTLPWKQCDNPWNTDRCFSNYSMV
  NTTNMTSAVVEFWERNMHQMTDGLDKPGQIRWPLAITLAIAWILVYFCIWKGVGWTGKVV
  YFSATYPYIMLIILFFRGVTLPGAKEGILFYITPNFRKLSDSEVWLDAATQIFFSYGLGL
  GSLIALGSYNSFHNNVYRDSIIVCCINSCTSMFAGFVIFSIVGFMAHVTKRSIADVAASG
  PGLAFLAYPEAVTQLPISPLWAILFFSMLLMLGIDSQFCTVEGFITALVDEYPRLLRNRR
  ELFIAAVCIISYLIGLSNITQGGIYVFKLFDYYSASGMSLLFLVFFECVSISWFYGVNRF
  YDNIQEMVGSRPCIWWKLCWSFFTPIIVAGVFIFSAVQMTPLTMGNYVFPKWGQGVGWLM
  ALSSMVLIPGYMAYMFLTLKGSLKQRIQVMVQPSEDIVRPENGPEQPQAGSSTSKEAYI
• Function: Mediates transport of gamma-aminobutyric acid (GABA) together with sodium and chloride and is responsible for the reuptake of GABA from the synapse. The translocation of GABA, however, may also occur in the reverse direction leading to the release of GABA. The direction and magnitude of GABA transport is a consequence of the prevailing thermodynamic conditions, determined by membrane potential and the intracellular and extracellular concentrations of Na(+), Cl(-) and GABA. Can also mediate sodium- and chloride-dependent transport of hypotaurine but to a much lower extent as compared to GABA.
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  GABAergic sy.pse (hsa04727)
• Reactome Pathway:
  Reuptake of GABA (R-HSA-888593)
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myoclonic-atonic epilepsy	DIS9DZIZ	Definitive	Autosomal dominant	[1]
Myoclonic-astatic epilepsy	DISTAVMU	Supportive	Unknown	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
GSK683699	DMTW79H	Phase 2	Sodium- and chloride-dependent GABA transporter 1 (SLC6A1) increases the uptake of GSK683699.	[10]

8 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 Sodium- and chloride-dependent GABA transporter 1 (SLC6A1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium- and chloride-dependent GABA transporter 1 (SLC6A1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium- and chloride-dependent GABA transporter 1 (SLC6A1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium- and chloride-dependent GABA transporter 1 (SLC6A1).	[3]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Sodium- and chloride-dependent GABA transporter 1 (SLC6A1).	[5]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of Sodium- and chloride-dependent GABA transporter 1 (SLC6A1).	[6]
Tiagabine	DMKSQG0	Approved	Tiagabine decreases the activity of Sodium- and chloride-dependent GABA transporter 1 (SLC6A1).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sodium- and chloride-dependent GABA transporter 1 (SLC6A1).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium- and chloride-dependent GABA transporter 1 (SLC6A1).	[9]

References

• [1] Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures. Am J Hum Genet. 2015 May 7;96(5):808-15.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [6] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [7] GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci. 2005 Mar 23;25(12):3234-45. doi: 10.1523/JNEUROSCI.3364-04.2005.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] Novel properties of a mouse gamma-aminobutyric acid transporter (GAT4). J Membr Biol. 2005 Jan;203(2):65-82. doi: 10.1007/s00232-004-0732-5.