Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRSPH8U)

• DOT Name: Excitatory amino acid transporter 4 (SLC1A6)
• Synonyms: Sodium-dependent glutamate/aspartate transporter; Solute carrier family 1 member 6
• Gene Name: SLC1A6
• UniProt ID: EAA4_HUMAN
• Pfam ID: PF00375
• Sequence:
  MSSHGNSLFLRESGQRLGRVGWLQRLQESLQQRALRTRLRLQTMTLEHVLRFLRRNAFIL
  LTVSAVVIGVSLAFALRPYQLTYRQIKYFSFPGELLMRMLQMLVLPLIVSSLVTGMASLD
  NKATGRMGMRAAVYYMVTTIIAVFIGILMVTIIHPGKGSKEGLHREGRIETIPTADAFMD
  LIRNMFPPNLVEACFKQFKTQYSTRVVTRTMVRTENGSEPGASMPPPFSVENGTSFLENV
  TRALGTLQEMLSFEETVPVPGSANGINALGLVVFSVAFGLVIGGMKHKGRVLRDFFDSLN
  EAIMRLVGIIIWYAPVGILFLIAGKILEMEDMAVLGGQLGMYTLTVIVGLFLHAGIVLPL
  IYFLVTHRNPFPFIGGMLQALITAMGTSSSSATLPITFRCLEEGLGVDRRITRFVLPVGA
  TVNMDGTALYEALAAIFIAQVNNYELNLGQITTISITATAASVGAAGIPQAGLVTMVIVL
  TSVGLPTEDITLIIAVDWFLDRLRTMTNVLGDSIGAAVIEHLSQRELELQEAELTLPSLG
  KPYKSLMAQEKGASRGRGGNESAM
• Function: Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate. Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion. Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport. Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate (Probable).
• Tissue Specificity: Brain, mainly in the cerebellum . Expressed densely and selectively in cell bodies of Purkinje cells.
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Glutamatergic sy.pse (hsa04724)
  Spinocerebellar ataxia (hsa05017)
• Reactome Pathway:
  Transport of inorganic cations/anions and amino acids/oligopeptides (R-HSA-425393)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Excitatory amino acid transporter 4 (SLC1A6).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Excitatory amino acid transporter 4 (SLC1A6).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Excitatory amino acid transporter 4 (SLC1A6).	[3]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Excitatory amino acid transporter 4 (SLC1A6).	[4]
Epanova	DMHEAGL	Approved	Epanova increases the expression of Excitatory amino acid transporter 4 (SLC1A6).	[5]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Excitatory amino acid transporter 4 (SLC1A6).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Excitatory amino acid transporter 4 (SLC1A6).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Excitatory amino acid transporter 4 (SLC1A6).	[9]

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 Excitatory amino acid transporter 4 (SLC1A6).	[7]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [4] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [5] Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells. Breast Cancer Res Treat. 2007 Jan;101(1):7-16. doi: 10.1007/s10549-006-9269-x. Epub 2006 Jul 6.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [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] 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.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.