Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQULEQ4)

• DOT Name: Vesicular glutamate transporter 3 (SLC17A8)
• Synonyms: VGluT3; Solute carrier family 17 member 8
• Gene Name: SLC17A8
• Related Disease:
  Nonsyndromic genetic hearing loss
  Autosomal dominant nonsyndromic hearing loss 25
  Autosomal dominant nonsyndromic hearing loss
• UniProt ID: VGLU3_HUMAN
• Pfam ID: PF07690
• Sequence:
  MPFKAFDTFKEKILKPGKEGVKNAVGDSLGILQRKIDGTTEEEDNIELNEEGRPVQTSRP
  SPPLCDCHCCGLPKRYIIAIMSGLGFCISFGIRCNLGVAIVEMVNNSTVYVDGKPEIQTA
  QFNWDPETVGLIHGSFFWGYIMTQIPGGFISNKFAANRVFGAAIFLTSTLNMFIPSAARV
  HYGCVMCVRILQGLVEGVTYPACHGMWSKWAPPLERSRLATTSFCGSYAGAVVAMPLAGV
  LVQYIGWSSVFYIYGMFGIIWYMFWLLQAYECPAAHPTISNEEKTYIETSIGEGANVVSL
  SKFSTPWKRFFTSLPVYAIIVANFCRSWTFYLLLISQPAYFEEVFGFAISKVGLLSAVPH
  MVMTIVVPIGGQLADYLRSRQILTTTAVRKIMNCGGFGMEATLLLVVGFSHTKGVAISFL
  VLAVGFSGFAISGFNVNHLDIAPRYASILMGISNGVGTLSGMVCPLIVGAMTRHKTREEW
  QNVFLIAALVHYSGVIFYGVFASGEKQEWADPENLSEEKCGIIDQDELAEEIELNHESFA
  SPKKKMSYGATSQNCEVQKKEWKGQRGATLDEEELTSYQNEERNFSTIS
• Function: Multifunctional transporter that transports L-glutamate as well as multiple ions such as chloride, sodium and phosphate. At the synaptic vesicle membrane, mainly functions as an uniporter that mediates the uptake of L-glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells. The L-glutamate uniporter activity is electrogenic and is driven by the proton electrochemical gradient, mainly by the electrical gradient established by the vacuolar H(+)-ATPase across the synaptic vesicle membrane. In addition, functions as a chloride channel that allows a chloride permeation through the synaptic vesicle membrane that affects the proton electrochemical gradient and promotes synaptic vesicles acidification. At the plasma membrane, following exocytosis, functions as a symporter of Na(+) and phosphate from the extracellular space to the cytoplasm allowing synaptic phosphate homeostasis regulation (Probable). The symporter activity is electrogenic. Moreover, operates synergistically with SLC18A3/VACHT under a constant H(+) gradient, thereby allowing striatal vesicular acetylcholine uptake.
• Tissue Specificity: Expressed in amygdala, cerebellum, hippocampus, medulla, spinal cord and thalamus.
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Nicotine addiction (hsa05033)
• Reactome Pathway:
  Defective SLC17A8 causes autosomal dominant deafness 25 (DFNA25) (R-HSA-5619076)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Organic anion transporters (R-HSA-428643)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal dominant	[1]
Autosomal dominant nonsyndromic hearing loss 25	DISNPE5M	Strong	Autosomal dominant	[2]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[3]

3 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 Vesicular glutamate transporter 3 (SLC17A8).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Vesicular glutamate transporter 3 (SLC17A8).	[5]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Vesicular glutamate transporter 3 (SLC17A8).	[6]

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 decreases the methylation of Vesicular glutamate transporter 3 (SLC17A8).	[7]

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] Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am J Hum Genet. 2008 Aug;83(2):278-92. doi: 10.1016/j.ajhg.2008.07.008.
• [3] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [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.