Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUOMMM6)

• DOT Name: Synaptic vesicular amine transporter (SLC18A2)
• Synonyms: Monoamine transporter; Solute carrier family 18 member 2; Vesicular amine transporter 2; VAT2
• Gene Name: SLC18A2
• Related Disease:
  Obsolete parkinsonism-dystonia, infantile, 2
  Brain dopamine-serotonin vesicular transport disease
  Schizophrenia
• UniProt ID: VMAT2_HUMAN
• PDB ID: 8JSW; 8JT9; 8JTA; 8JTC; 8T69; 8T6A; 8T6B; 8THR
• Pfam ID: PF07690
• Sequence:
  MALSELALVRWLQESRRSRKLILFIVFLALLLDNMLLTVVVPIIPSYLYSIKHEKNATEI
  QTARPVHTASISDSFQSIFSYYDNSTMVTGNATRDLTLHQTATQHMVTNASAVPSDCPSE
  DKDLLNENVQVGLLFASKATVQLITNPFIGLLTNRIGYPIPIFAGFCIMFVSTIMFAFSS
  SYAFLLIARSLQGIGSSCSSVAGMGMLASVYTDDEERGNVMGIALGGLAMGVLVGPPFGS
  VLYEFVGKTAPFLVLAALVLLDGAIQLFVLQPSRVQPESQKGTPLTTLLKDPYILIAAGS
  ICFANMGIAMLEPALPIWMMETMCSRKWQLGVAFLPASISYLIGTNIFGILAHKMGRWLC
  ALLGMIIVGVSILCIPFAKNIYGLIAPNFGVGFAIGMVDSSMMPIMGYLVDLRHVSVYGS
  VYAIADVAFCMGYAIGPSAGGAIAKAIGFPWLMTIIGIIDILFAPLCFFLRSPPAKEEKM
  AILMDHNCPIKTKMYTQNNIQSYPIGEDEESESD
• Function: Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles. Uses the electrochemical proton gradient established by the V-type proton-pump ATPase to accumulate high concentrations of monoamines inside the vesicles prior to their release via exocytosis. Transports a variety of catecholamines such as dopamine, adrenaline and noradrenaline, histamine, and indolamines such as serotonin. Regulates the transvesicular monoaminergic gradient that determines the quantal size. Mediates somatodendritic dopamine release in hippocampal neurons, likely as part of a regulated secretory pathway that integrates retrograde synaptic signals. Acts as a primary transporter for striatal dopamine loading ensuring impulse-dependent release of dopamine at the synaptic cleft. Responsible for histamine and serotonin storage and subsequent corelease from mast cell granules.
• Tissue Specificity: Expressed in neuronal and neuroendocrine tissues. Detected in central and peripheral nervous system in particular in axonal and dendritic processes in dopaminergic cells of substantia nigra, histaminergic neuronal cell bodies of substantia nigra and tuberomammillary nucleus, in ganglion cells of sympathetic glia and in peripheral sympathetic nerve terminals in stomach and duodenum (at protein level). Highly expressed in chromaffin cells of the adrenal medulla and histamine-storing enterochromaffin-like cells of oxyntic mucosa (at protein level).
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Serotonergic sy.pse (hsa04726)
  Dopaminergic sy.pse (hsa04728)
  Parkinson disease (hsa05012)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
• Reactome Pathway:
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Serotonin Neurotransmitter Release Cycle (R-HSA-181429)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete parkinsonism-dystonia, infantile, 2	DIS1UZ1T	Strong	Autosomal recessive	[1]
Brain dopamine-serotonin vesicular transport disease	DISQKVW8	Supportive	Autosomal recessive	[1]
Schizophrenia	DISSRV2N	No Known	Unknown	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Reserpine	DM6VM38	Approved	Synaptic vesicular amine transporter (SLC18A2) decreases the response to substance of Reserpine.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Serotonin	DMOFCRY	Investigative	Synaptic vesicular amine transporter (SLC18A2) affects the uptake of Serotonin.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Synaptic vesicular amine transporter (SLC18A2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Synaptic vesicular amine transporter (SLC18A2).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Synaptic vesicular amine transporter (SLC18A2).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Synaptic vesicular amine transporter (SLC18A2).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Synaptic vesicular amine transporter (SLC18A2).	[6]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Synaptic vesicular amine transporter (SLC18A2).	[7]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the activity of Synaptic vesicular amine transporter (SLC18A2).	[8]
Dopamine	DMPGUCF	Approved	Dopamine decreases the activity of Synaptic vesicular amine transporter (SLC18A2).	[10]
Norepinephrine	DMOUC09	Approved	Norepinephrine decreases the activity of Synaptic vesicular amine transporter (SLC18A2).	[10]
Tetrabenazine	DMYWQ0O	Approved	Tetrabenazine decreases the activity of Synaptic vesicular amine transporter (SLC18A2).	[10]
Ingrezza	DMVPLNC	Phase 4	Ingrezza decreases the activity of Synaptic vesicular amine transporter (SLC18A2).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Synaptic vesicular amine transporter (SLC18A2).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Synaptic vesicular amine transporter (SLC18A2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Synaptic vesicular amine transporter (SLC18A2).	[15]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the activity of Synaptic vesicular amine transporter (SLC18A2).	[8]

6 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Haloperidol	DM96SE0	Approved	Haloperidol affects the binding of Synaptic vesicular amine transporter (SLC18A2).	[9]
Ergotidine	DM78IME	Approved	Ergotidine affects the binding of Synaptic vesicular amine transporter (SLC18A2).	[9]
Dextroamphetamine	DMMIHVP	Approved	Dextroamphetamine affects the binding of Synaptic vesicular amine transporter (SLC18A2).	[9]
Mazindol	DMZ36RN	Approved	Mazindol affects the binding of Synaptic vesicular amine transporter (SLC18A2).	[9]
Nomifensine	DMCP2TS	Withdrawn from market	Nomifensine affects the binding of Synaptic vesicular amine transporter (SLC18A2).	[9]
Vanoxerine	DMBQPA5	Discontinued in Phase 1	Vanoxerine affects the binding of Synaptic vesicular amine transporter (SLC18A2).	[9]

References

• [1] Brain dopamine-serotonin vesicular transport disease and its treatment. N Engl J Med. 2013 Feb 7;368(6):543-50. doi: 10.1056/NEJMoa1207281. Epub 2013 Jan 30.
• [2] Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell. 2013 Aug 1;154(3):518-29. doi: 10.1016/j.cell.2013.06.049.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] 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.
• [5] 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.
• [6] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [7] Loss of striatal vesicular monoamine transporter protein (VMAT2) in human cocaine users. Am J Psychiatry. 2003 Jan;160(1):47-55. doi: 10.1176/appi.ajp.160.1.47.
• [8] Assessing Vesicular Monoamine Transport and Toxicity Using Fluorescent False Neurotransmitters. Chem Res Toxicol. 2021 May 17;34(5):1256-1264. doi: 10.1021/acs.chemrestox.0c00380. Epub 2020 Dec 30.
• [9] Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile. Brain Res Mol Brain Res. 1994 Mar;22(1-4):219-26. doi: 10.1016/0169-328x(94)90050-7.
• [10] The effect of rare human sequence variants on the function of vesicular monoamine transporter 2. Pharmacogenetics. 2004 Sep;14(9):587-94. doi: 10.1097/00008571-200409000-00003.
• [11] Valbenazine in the treatment of tardive dyskinesia. Neurodegener Dis Manag. 2019 Apr;9(2):73-81. doi: 10.2217/nmt-2019-0001. Epub 2019 Feb 6.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] 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.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.