Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAUUY4B)

• DOT Name: Vesicular acetylcholine transporter (SLC18A3)
• Synonyms: VAChT; Solute carrier family 18 member 3
• Gene Name: SLC18A3
• Related Disease:
  Congenital myasthenic syndrome 21
  Fetal akinesia deformation sequence 1
  Obsolete presynaptic congenital myasthenic syndrome
• UniProt ID: VACHT_HUMAN
• Pfam ID: PF07690
• Sequence:
  MESAEPAGQARAAATKLSEAVGAALQEPRRQRRLVLVIVCVALLLDNMLYMVIVPIVPDY
  IAHMRGGGEGPTRTPEVWEPTLPLPTPANASAYTANTSASPTAAWPAGSALRPRYPTESE
  DVKIGVLFASKAILQLLVNPLSGPFIDRMSYDVPLLIGLGVMFASTVLFAFAEDYATLFA
  ARSLQGLGSAFADTSGIAMIADKYPEEPERSRALGVALAFISFGSLVAPPFGGILYEFAG
  KRVPFLVLAAVSLFDALLLLAVAKPFSAAARARANLPVGTPIHRLMLDPYIAVVAGALTT
  CNIPLAFLEPTIATWMKHTMAASEWEMGMAWLPAFVPHVLGVYLTVRLAARYPHLQWLYG
  ALGLAVIGASSCIVPACRSFAPLVVSLCGLCFGIALVDTALLPTLAFLVDVRHVSVYGSV
  YAIADISYSVAYALGPIVAGHIVHSLGFEQLSLGMGLANLLYAPVLLLLRNVGLLTRSRS
  ERDVLLDEPPQGLYDAVRLRERPVSGQDGEPRSPPGPFDACEDDYNYYYTRS
• Function: Electrogenic antiporter that exchanges one cholinergic neurotransmitter, acetylcholine or choline, with two intravesicular protons across the membrane of synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to store neurotransmitters inside the vesicles prior to their release via exocytosis. Determines cholinergic vesicular quantal size at presynaptic nerve terminals in developing neuro-muscular junctions with an impact on motor neuron differentiation and innervation pattern. Part of forebrain cholinergic system, regulates hippocampal synapse transmissions that underlie spatial memory formation. Can transport serotonin.
• Tissue Specificity: Peripheral and central cholinergic nervous systems.
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Cholinergic sy.pse (hsa04725)
• Reactome Pathway:
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Acetylcholine Neurotransmitter Release Cycle (R-HSA-264642)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome 21	DISAG46U	Strong	Autosomal recessive	[1]
Fetal akinesia deformation sequence 1	DISKDI9L	Supportive	Autosomal recessive	[2]
Obsolete presynaptic congenital myasthenic syndrome	DISCATK3	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 affects the expression of Vesicular acetylcholine transporter (SLC18A3).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Vesicular acetylcholine transporter (SLC18A3).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Vesicular acetylcholine transporter (SLC18A3).	[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 increases the methylation of Vesicular acetylcholine transporter (SLC18A3).	[7]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] SLC18A3 variants lead to fetal akinesia deformation sequence early in pregnancy. Am J Med Genet A. 2019 Jul;179(7):1362-1365. doi: 10.1002/ajmg.a.61186. Epub 2019 May 6.
• [3] Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome. Neurology. 2016 Oct 4;87(14):1442-1448. doi: 10.1212/WNL.0000000000003179. Epub 2016 Sep 2.
• [4] 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.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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.