SLC18A2

Summary

SLC18A2 (solute carrier family 18 member A2, HGNC:10935) is a protein-coding gene on chromosome 10q25.3, encoding Synaptic vesicular amine transporter (Q05940). Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles.

This gene encodes an transmembrane protein that functions as an ATP-dependent transporter of monoamines, such as dopamine, norepinephrine, serotonin, and histamine. This protein transports amine neurotransmitters into synaptic vesicles. Polymorphisms in this gene may be associated with schizophrenia, bipolar disorder, and other neurological/psychiatric ailments.

Source: NCBI Gene 6571 — RefSeq curated summary.

At a glance

• Gene–disease (curated): brain dopamine-serotonin vesicular transport disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 250 total — 6 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 45
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003054

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10935
Approved symbol	SLC18A2
Name	solute carrier family 18 member A2
Location	10q25.3
Locus type	gene with protein product
Status	Approved
Aliases	SVMT, SVAT, VAT2
Ensembl gene	ENSG00000165646
Ensembl biotype	protein_coding
OMIM	193001
Entrez	6571

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 retained_intron

ENST00000497497, ENST00000644641, ENST00000853677, ENST00000853678, ENST00000853679, ENST00000921156, ENST00000921157, ENST00000921158, ENST00000921159, ENST00000956273

RefSeq mRNA: 1 — MANE Select: NM_003054 NM_003054

CCDS: CCDS7599

Canonical transcript exons

ENST00000644641 — 16 exons

Exon	Start	End
ENSE00001095017	117254405	117254497
ENSE00001220843	117254048	117254131
ENSE00003459343	117255277	117255366
ENSE00003488968	117277162	117279430
ENSE00003497038	117255479	117255522
ENSE00003512334	117270330	117270463
ENSE00003519088	117266984	117267035
ENSE00003535846	117255597	117255657
ENSE00003555225	117241679	117241814
ENSE00003584522	117270071	117270190
ENSE00003587036	117243971	117244313
ENSE00003587584	117257797	117257892
ENSE00003622984	117267673	117267736
ENSE00003658472	117266733	117266811
ENSE00003668337	117253399	117253457
ENSE00003830069	117241114	117241220

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 97.05.

FANTOM5 (CAGE): breadth broad, TPM avg 4.4394 / max 1036.2484, expressed in 197 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107255	3.2899	156
107257	0.6814	70
107256	0.3317	51
107254	0.1365	27

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
substantia nigra pars reticulata	UBERON:0001966	97.05	gold quality
substantia nigra pars compacta	UBERON:0001965	92.94	gold quality
secondary oocyte	CL:0000655	88.10	gold quality
tibia	UBERON:0000979	84.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.06	gold quality
substantia nigra	UBERON:0002038	83.21	gold quality
oocyte	CL:0000023	82.35	gold quality
skin of hip	UBERON:0001554	81.24	gold quality
midbrain	UBERON:0001891	80.59	gold quality
islet of Langerhans	UBERON:0000006	80.07	gold quality
endometrium	UBERON:0001295	78.73	gold quality
type B pancreatic cell	CL:0000169	76.03	gold quality
gall bladder	UBERON:0002110	75.91	gold quality
ectocervix	UBERON:0012249	74.53	gold quality
vagina	UBERON:0000996	73.94	gold quality
body of stomach	UBERON:0001161	73.76	gold quality
superior vestibular nucleus	UBERON:0007227	73.66	gold quality
upper leg skin	UBERON:0004262	73.07	gold quality
decidua	UBERON:0002450	71.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.38	gold quality
rectum	UBERON:0001052	71.38	gold quality
fundus of stomach	UBERON:0001160	71.27	gold quality
pancreas	UBERON:0001264	71.25	gold quality
prostate gland	UBERON:0002367	71.06	gold quality
endocervix	UBERON:0000458	70.98	gold quality
uterine cervix	UBERON:0000002	70.96	gold quality
right lung	UBERON:0002167	70.76	gold quality
stomach	UBERON:0000945	70.36	gold quality
left ovary	UBERON:0002119	70.32	gold quality
uterus	UBERON:0000995	70.20	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	3299.21
E-GEOD-130473	yes	1587.82
E-HCAD-24	yes	1265.08
E-MTAB-9067	yes	1166.16
E-HCAD-25	yes	994.25
E-CURD-112	yes	615.95
E-HCAD-1	yes	39.19
E-CURD-88	yes	32.04
E-ANND-3	yes	19.40
E-MTAB-8410	yes	17.36
E-GEOD-130148	yes	16.07
E-CURD-122	yes	14.75
E-HCAD-10	yes	11.21
E-MTAB-10042	yes	10.49
E-GEOD-81547	yes	10.35

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EN1, NR4A2, PARK7, PITX3, PREB

miRNA regulators (miRDB)

127 targeting SLC18A2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163

Literature-anchored findings (GeneRIF, showing 40)

• Assessment of the VMAT2 thrombin cleavage site reveals that the Cys-126 in loop 1/2 and Cys-333 in loop 7/8 form a disulfide bond which contributes to efficient monoamine transport. (PMID:12009896)
• Striatal VMAT2 expression was reduced significantly in dementia with Lewy bodies with or without Alzheimer’s disease, but was preserved in Alzheimer’s disease striatum, permitting postmortem distinction of the two pathologies. (PMID:12112084)
• striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes in addition to its importance for the quantal release of monoamines. (PMID:12710012)
• vesicular monoamine transporter (VMAT2) mRNA was not detected in the central part of the placenta but was present in the spiral arteries of placenta bed biopsies (PMID:15135235)
• two single nucleotide polymorphisms were identified that have no detectable effect on most aspects of VMAT2 function, but one may increase sensitivity to the inhibitor tetrabenazine (PMID:15475732)
• SLC18A2 promoter haplotypes defined here create a foundation for transcriptional characterization of individuality and for association study on monoamine-related human diseases (PMID:15829504)
• VMAT2 pharmacodynamic characteristics in a population of medicated schizophrenia patients comparing smokers and nonsmokers. (PMID:16139173)
• Greater expression of VMAT 1 in von Hippel-Lindau syndrome than multiple endocrine neoplasia type 2. Expression of VMAT 2 did not differ significantly. (PMID:16189177)
• Gain-of-function haplotypes in the SLC18A2 promoter are protective for Parkinson disease in women. (PMID:16339215)
• Low expression of VMAT2 in the substantia nigra of Parkinson’s disease , the involvement of VMAT2 in Lewy body of the substantia nigra suggests the association of this protein in the neurodegeneration of nigral neurons in Parkinson’s disease. (PMID:16386370)
• VMAT 2 antibodies seem more useful for histopathological diagnosis of enterochromaffin-like cell neoplasms than the antibodies to the other CgA regions. (PMID:16408221)
• This review summarizes the possible role of VMAT2 as a therapeutic target and discusses the structure-activity relationships and binding relevance of the VMAT2 ligands reported in the literature. (PMID:17233532)
• lower platelet VMAT2 density occurred in the brain and may serve as an adaptive mechanism geared to decrease dopamine storage (PMID:17344033)
• These results strongly suggest that SVMT gene or certain regions of it may constitute a genetic substrate of susceptibility for both schizophrenia and bipolar disorder. (PMID:17427184)
• data suggest that elements of the 20 S proteasome interact with the VMAT2 promoter to enhance G-protein-coupled receptor-mediated transcription (PMID:17442673)
• Mishandling of dopamine via reduced VMAT2 transgenic expression causes dopamine-mediated toxicity and neurodegeneration in the mouse nigrostriatal dopamine system, replicating key aspects of Parkinson’s disease. (PMID:17652604)
• review of the regulation of VMAT2 and the state of the understanding of what measurements of VMAT2 density mean in the context of diabetes (PMID:17665159)
• These data suggest that up-regulated alpha-synuclein expression inhibits the activity of vesicular monoamine transporter-2. (PMID:17985233)
• Variation in SLC18A2 is implicated as risk factor for schizophrenia. (PMID:18045777)
• variation in the VMAT2 gene plays a role in one’s openness to spiritual experiences (PMID:18316816)
• Rotenone redistributes VMAT2 via nitration in dopaminergic SH-SY5Y cells. (PMID:18599602)
• Most beta cells expressed VMAT2. VMAT2 expression was not changed by the presence of diabetes. (PMID:18791800)
• SLC18A2 silencing by DNA hypermethylation and/or allelic loss is a frequent event in prostate cancer and a novel independent predictor of biochemical recurrence after prostatectomy (PMID:19228741)
• Obestatin and ghrelin immunoreactivity always occurred in the same endocrine cells in the gastric mucosa but these cells only occasionally co-expressed VMAT-2, opposite to the findings in tumours. (PMID:19289536)
• Voxel-based analysis demonstrated VMAT2 reductions in the striatum and mid brain of Parkinson disease patients. (PMID:20080893)
• greater diversity of transcriptional regulations is the driving force for the haplotype selection in SLC18A2 (PMID:20181938)
• Six electroconvulsive therapy sessions are not sufficient for modulation in pVMAT2 expression. Long-term studies are needed to clarify the relationship between full remission and possible alterations in platelet/brain VMAT2 characteristics. (PMID:20544232)
• A significant reduction of platelet VMAT2 mRNA levels was demonstrated in Parkinson Disease patients versus healthy controls (PMID:20665056)
• This preliminary finding indicates a possible structural change in platelet VMAT2 in children with major depressive disorder. (PMID:21484276)
• Distribution of vesicular monoamine transporter 2 protein in human brain: implications for brain imaging studies. (PMID:21522164)
• In an aversive ultrasound-induced defense paradigm, VMAT2(sert-cre) transgenic mice displayed a major increase in escape-like behaviors. (PMID:21814181)
• there is no difference in levels of vesicular monoamine transporter 2 between children with disruptive behavior disorders and healthy volunteers (PMID:21851191)
• These results support our hypothesis that VMAT-2 and DT-diaphorase are an important defense system against aminochrome formed during dopamine oxidation. (PMID:22483869)
• Genetic variation in VMAT2 may be linked to alterations in cognitive functioning underlying psychotic disorder, possibly through altered transport of monoamines into synaptic vesicles. (PMID:22532702)
• These results indicate that wild-type DJ-1, but not Parkinson’s disease-derived mutant DJ-1, stimulates VMAT2 activity and that C106 is necessary for the stimulating activity of DJ-1 toward VMAT2. (PMID:22554508)
• analysis of Dopamine D1, D2, D3 receptors, vesicular monoamine transporter type-2 (VMAT2) and dopamine transporter (DAT) densities in aged human brain (PMID:23185343)
• Study evaluated VMAT2 specificity for beta cells in sub-regions of the human pancreas using antibodies targeting VMAT2, insulin and PP by double-label immunofluorescence. (PMID:23221614)
• describe a disease encompassing infantile-onset movement disorder and evidence supporting its causation by a mutation in SLC18A2 (which encodes vesicular monoamine transporter 2 [VMAT2]) (PMID:23363473)
• In an Italian cohort, variability in VMAT2 promoter region appears to confer a reduced risk of developing Parkinson’s disease. (PMID:23369548)
• Data suggest that pancreatic islets of humans and pigs contain VMAT2 in similar patterns (in beta cells, mast cells, and sympathetic neurons); therefore, the pig (unlike rodents) is potential model for imaging pancreas using radioligands for VMAT2. (PMID:23404442)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc18a2	ENSDARG00000015110
mus_musculus	Slc18a2	ENSMUSG00000025094
rattus_norvegicus	Slc18a2	ENSRNOG00000008890
caenorhabditis_elegans		WBGENE00012280
caenorhabditis_elegans		WBGENE00013996

Paralogs (3): SLC18A1 (ENSG00000036565), SLC18B1 (ENSG00000146409), SLC18A3 (ENSG00000187714)

Protein

Protein identifiers

Synaptic vesicular amine transporter — Q05940 (reviewed: Q05940)

Alternative names: Solute carrier family 18 member 2, Vesicular amine transporter 2, Vesicular monoamine transporter 2

All UniProt accessions (1): Q05940

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Interacts with SLC6A3.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Secretory vesicle membrane. Cell projection. Axon. Dendrite.

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).

Disease relevance. Parkinsonism-dystonia 2, infantile-onset (PKDYS2) [MIM:618049] An autosomal recessive disorder characterized by infantile onset of abnormal movements, including parkinsonism, dystonia, and poor fine motor skills, as well as autonomic dysfunction, including abnormal sweating, cold extremities, and poor sleep. Some patients have variable degrees of developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Strongly inhibited by reserpine and tetrabenazine. Also inhibited to a lesser extent by ketanserin and fenfluramine. Reserpine and ketanserin inhibit by blocking the substrate-binding pocket. Tetrabenazine traps SLC18A2/VMAT2 in an occluded conformation and its inhibition is specific to SLC18A2/VMAT2 but not SLC18A1/VMAT1.

Similarity. Belongs to the major facilitator superfamily. Vesicular transporter family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q05940-1	1	yes
Q05940-2	2

RefSeq proteins (1): NP_003045* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011701	MFS	Family
IPR020846	MFS_dom	Domain
IPR036259	MFS_trans_sf	Homologous_superfamily
IPR050930	MFS_Vesicular_Transporter	Family

Pfam: PF07690

Catalyzed reactions (Rhea), 3 shown:

• dopamine(in) + 2 H(+)(out) = dopamine(out) + 2 H(+)(in) (RHEA:73739)
• serotonin(in) + 2 H(+)(out) = serotonin(out) + 2 H(+)(in) (RHEA:73743)
• histamine(in) + 2 H(+)(out) = histamine(out) + 2 H(+)(in) (RHEA:73755)

UniProt features (128 total): mutagenesis site 61, helix 18, topological domain 13, transmembrane region 12, binding site 9, sequence conflict 5, modified residue 2, glycosylation site 2, splice variant 2, chain 1, turn 1, disulfide bond 1, sequence variant 1

Structure

Experimental structures (PDB)

32 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8JSW	ELECTRON MICROSCOPY	2.84
8T69	ELECTRON MICROSCOPY	2.89
8WRE	ELECTRON MICROSCOPY	2.9
8JTB	ELECTRON MICROSCOPY	2.93
8JT9	ELECTRON MICROSCOPY	2.97
8X3K	ELECTRON MICROSCOPY	2.98
9KQE	ELECTRON MICROSCOPY	3
8XOA	ELECTRON MICROSCOPY	3.03
8WRD	ELECTRON MICROSCOPY	3.05
8JT5	ELECTRON MICROSCOPY	3.06
8THR	ELECTRON MICROSCOPY	3.12
8UCM	ELECTRON MICROSCOPY	3.14
8XOB	ELECTRON MICROSCOPY	3.15
8JSX	ELECTRON MICROSCOPY	3.16
8T6A	ELECTRON MICROSCOPY	3.17
8UCL	ELECTRON MICROSCOPY	3.18
8WVG	ELECTRON MICROSCOPY	3.18
8UCJ	ELECTRON MICROSCOPY	3.2
8XO9	ELECTRON MICROSCOPY	3.2
8UCO	ELECTRON MICROSCOPY	3.25
8UCK	ELECTRON MICROSCOPY	3.26
8UCP	ELECTRON MICROSCOPY	3.28
9KQA	ELECTRON MICROSCOPY	3.28
8UCN	ELECTRON MICROSCOPY	3.31
8JTA	ELECTRON MICROSCOPY	3.36
8WLK	ELECTRON MICROSCOPY	3.37
9KQ8	ELECTRON MICROSCOPY	3.38
8JTC	ELECTRON MICROSCOPY	3.52
8WLM	ELECTRON MICROSCOPY	3.57
8WLJ	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05940-F1	77.27	0.47

Antibody-complex structures (SAbDab): 4 — 8WLJ, 8WRD, 8WRE, 8WVG

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (9): 228; 232; 305; 308; 312; 334; 341; 399; 433

Post-translational modifications (2): 511, 513

Disulfide bonds (1): 117–324

Glycosylation sites (2): 84, 91

Mutagenesis-validated functional residues (61):

Position	Phenotype
426	abolishes dopamine uptake. abolishes serotonin uptake.
429	abolishes binding to reserpine. reduces serotonin uptake.
433	abolishes binding to dihydrotetrabenazine. slightly reduces binding to reserpine and ffn206 uptake. reduces dopamine upt
433	slightly reduces sensitivity to tetrabenazine and ffn206 uptake. reduces serotonin uptake. reduces sensitivity to reserp
33	abolishes dopamine uptake.
33	abolishes dopamine uptake. abolishes serotonin uptake.
34	abolishes binding to reserpine. reduces binding to dihydrotetrabenazine. reduces serotonin uptake.
34	abolishes binding to dihydrotetrabenazine. reduces serotonin uptake.
34	reduces binding to dihydrotetrabenazine.
34	abolishes binding to dihydrotetrabenazine. abolishes serotonin uptake.
37	abolishes binding to dihydrotetrabenazine.
37	reduces sensitivity to tetrabenazine. reduces fluorescent false neurotransmitter ffn206 uptake. abolishes binding to dih
37	abolishes binding to tetrabenazine. reduces sensitivity to tetrabenazine.
38	abolishes binding to dihydrotetrabenazine. abolishes dopamine uptake.
41	abolishes binding to dihydrotetrabenazine. reduces dopamine uptake.
45	abolishes dopamine uptake.
127	reduces serotonin uptake.
135	abolishes binding to dihydrotetrabenazine. reduces sensitivity to tetrabenazine. abolishes ffn206 uptake. abolishes bind
138	reduces dopamine uptake. abolishes binding to dihydrotetrabenazine. abolishes serotonin uptake.
189	abolishes binding to dihydrotetrabenazine. abolishes serotonin uptake.
189	abolishes binding to dihydrotetrabenazine. abolishes binding to tetrabenazine. abolishes serotonin uptake.
189	abolishes serotonin uptake.
196	reduces dopamine uptake.
204	reduces dopamine uptake.
214	abolishes serotonin uptake; when associated with a-217.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-181429	Serotonin Neurotransmitter Release Cycle
R-HSA-181430	Norepinephrine Neurotransmitter Release Cycle
R-HSA-212676	Dopamine Neurotransmitter Release Cycle
R-HSA-442660	SLC-mediated transport of neurotransmitters

MSigDB gene sets: 337 (showing top): ATF_B, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_AMINE, GOBP_NEUROTRANSMITTER_UPTAKE, GOBP_INFLAMMATORY_RESPONSE, RORA1_01, GOCC_SECRETORY_GRANULE, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, MODULE_64, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_HORMONE_TRANSPORT, CREBP1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (21): response to amphetamine (GO:0001975), serotonin secretion by mast cell (GO:0002552), histamine secretion by mast cell (GO:0002553), neurotransmitter transport (GO:0006836), chemical synaptic transmission (GO:0007268), locomotory behavior (GO:0007626), response to toxic substance (GO:0009636), post-embryonic development (GO:0009791), aminergic neurotransmitter loading into synaptic vesicle (GO:0015842), obsolete monoamine transport (GO:0015844), obsolete dopamine transport (GO:0015872), serotonin uptake (GO:0051610), histamine uptake (GO:0051615), neurotransmitter loading into synaptic vesicle (GO:0098700), somato-dendritic dopamine secretion (GO:0099123), negative regulation of reactive oxygen species biosynthetic process (GO:1903427), obsolete serotonin transport (GO:0006837), xenobiotic transport (GO:0042908), establishment of localization in cell (GO:0051649), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600)

GO Molecular Function (6): serotonin:sodium:chloride symporter activity (GO:0005335), monoamine transmembrane transporter activity (GO:0008504), monoamine:proton antiporter activity (GO:0015311), protein binding (GO:0005515), transmembrane transporter activity (GO:0022857), xenobiotic transmembrane transporter activity (GO:0042910)

GO Cellular Component (15): centrosome (GO:0005813), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), secretory granule membrane (GO:0030667), synaptic vesicle membrane (GO:0030672), terminal bouton (GO:0043195), clathrin-sculpted monoamine transport vesicle membrane (GO:0070083), dopaminergic synapse (GO:0098691), transport vesicle membrane (GO:0030658), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Neurotransmitter release cycle	3
SLC-mediated transmembrane transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
establishment of localization in cell	4
transport	3
mast cell degranulation	2
exocytic process	2
monoamine transmembrane transporter activity	2
presynapse	2
cellular anatomical structure	2
neuron projection	2
cytoplasmic vesicle membrane	2
bounding membrane of organelle	2
response to amine	1
serotonin secretion involved in inflammatory response	1
histamine secretion involved in inflammatory response	1
anterograde trans-synaptic signaling	1
behavior	1
response to chemical	1
multicellular organism development	1
multicellular organismal process	1
amine transport	1
neurotransmitter loading into synaptic vesicle	1
organic hydroxy compound transport	1
nitrogen compound transport	1
neurotransmitter reuptake	1
neurotransmitter uptake	1
histamine transport	1
neurotransmitter transport	1
intercellular transport	1
synaptic vesicle cycle	1
dopamine secretion	1
somatodendritic compartment	1
negative regulation of biosynthetic process	1
reactive oxygen species biosynthetic process	1
regulation of reactive oxygen species biosynthetic process	1
negative regulation of reactive oxygen species metabolic process	1
establishment of localization	1
cellular localization	1
cellular process	1
sodium:chloride symporter activity	1
serotonin uptake	1
active transmembrane transporter activity	1

Protein interactions and networks

STRING

1408 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC18A2	DDC	P20711	965
SLC18A2	TH	P07101	964
SLC18A2	SLC6A3	Q01959	950
SLC18A2	SLC29A4	Q7RTT9	932
SLC18A2	SLC6A4	P31645	881
SLC18A2	DRD2	P14416	814
SLC18A2	SNCA	P37840	806
SLC18A2	SLC6A2	P23975	805
SLC18A2	NR4A2	P43354	802
SLC18A2	MAOA	P21397	793
SLC18A2	MAOB	P27338	792
SLC18A2	TPH2	Q8IWU9	707
SLC18A2	DBH	P09172	700
SLC18A2	PITX3	O75364	699
SLC18A2	KCNJ6	P48051	693

IntAct

34 interactions, top by confidence:

A	B	Type	Score
GPR151	SLC18A2	psi-mi:“MI:0915”(physical association)	0.560
SLC18A2	GPR151	psi-mi:“MI:0915”(physical association)	0.560
SLC18A2	MFSD5	psi-mi:“MI:0915”(physical association)	0.560
SLC18A2	CFHR5	psi-mi:“MI:0915”(physical association)	0.560
SLC18A2	BRICD5	psi-mi:“MI:0915”(physical association)	0.560
SLC18A2	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
SLC18A2	NKG7	psi-mi:“MI:0915”(physical association)	0.560
CXCR2	SLC18A2	psi-mi:“MI:0915”(physical association)	0.560
SLC7A1	SLC18A2	psi-mi:“MI:0915”(physical association)	0.560
SLC18A2	TOMM6	psi-mi:“MI:0915”(physical association)	0.560
SLC18A2	TMEM109	psi-mi:“MI:0915”(physical association)	0.560
SLC18A2	UBXN8	psi-mi:“MI:0914”(association)	0.350
SLC18A2	MGST3	psi-mi:“MI:0914”(association)	0.350
SLC18A2	LGALS8	psi-mi:“MI:0914”(association)	0.350
MFSD5	SLC18A2	psi-mi:“MI:0915”(physical association)	0.000
CFHR5	SLC18A2	psi-mi:“MI:0915”(physical association)	0.000
BRICD5	SLC18A2	psi-mi:“MI:0915”(physical association)	0.000
CMTM5	SLC18A2	psi-mi:“MI:0915”(physical association)	0.000
NKG7	SLC18A2	psi-mi:“MI:0915”(physical association)	0.000
SLC7A1	SLC18A2	psi-mi:“MI:0915”(physical association)	0.000
TOMM6	SLC18A2	psi-mi:“MI:0915”(physical association)	0.000
CXCR2	SLC18A2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (137): DNAJC5 (FRET), SLC18A2 (Two-hybrid), SLC18A2 (Two-hybrid), SLC18A2 (Two-hybrid), SLC18A2 (Two-hybrid), CMTM5 (Two-hybrid), GPR151 (Two-hybrid), CXCR2 (Two-hybrid), MFSD5 (Two-hybrid), BRICD5 (Two-hybrid), TOMM6 (Two-hybrid), SLC18A2 (Affinity Capture-Western), NEK7 (Affinity Capture-MS), MZT2B (Affinity Capture-MS), TRAPPC2 (Affinity Capture-MS)

ESM2 similar proteins: A2VE55, A6NI61, A6QQL0, A6QQX9, A9CMA6, B0UY98, B8B7Q4, D3ZG27, F2Z4R5, F4JN00, O14494, O70496, O88956, P51798, P51799, P60588, P93394, Q01827, Q05940, Q0VBU9, Q1JQC1, Q27963, Q32LQ6, Q5QJU3, Q5R8G5, Q5RDC9, Q5VZY2, Q5XF09, Q5ZJH8, Q6DBP3, Q6DHK8, Q6GLN7, Q6GR34, Q6IP19, Q6PBE5, Q6ZL17, Q8BRU6, Q8BWB6, Q8C996, Q8GUJ1

Diamond homologs: A0A0U2UXG3, A0A254TZW7, A0A345BJP9, A0A348HAX9, A0A3G1DIJ8, A0A3G1DIQ9, B8MKZ1, B8MKZ7, G3Y4N5, O34307, O74852, P32482, P38227, Q05940, Q59YT1, Q5A6P6, Q6FNQ2, A0A166Z003, A0A455ZIM5, O17444, O35304, P39886, P54219, P81721, Q01827, Q08C75, Q16572, Q27963, Q62666, Q8BRU6, Q91498, Q91514, P34711, P59845, P9WJY4, P9WJY5, Q01818, Q8R090, P32369, P33449

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
reserpine	“down-regulates activity”	SLC18A2	“chemical inhibition”
tetrabenazine	“down-regulates activity”	SLC18A2	“chemical inhibition”
ketanserin	“down-regulates activity”	SLC18A2	“chemical inhibition”
SLC18A2	“up-regulates activity”	BLOC-1	binding
SLC18A2	“up-regulates quantity”	dopamine	relocalization
CSNK1A1	unknown	SLC18A2	phosphorylation
CSNK2A1	unknown	SLC18A2	phosphorylation
CSNK2A2	unknown	SLC18A2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

250 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	6
Uncertain significance	97
Likely benign	102
Benign	27

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1363175	NM_003054.6(SLC18A2):c.424C>T (p.Gln142Ter)	Pathogenic
1919082	NM_003054.6(SLC18A2):c.216dup (p.Asp73fs)	Pathogenic
2060871	NM_003054.6(SLC18A2):c.605del (p.Ala202fs)	Pathogenic
2664950	NM_003054.6(SLC18A2):c.240_244del (p.Ser80_Tyr81insTer)	Pathogenic
2793810	NM_003054.6(SLC18A2):c.46_55del (p.Arg16fs)	Pathogenic
520810	NM_003054.4(SLC18A2):c.835_836delAG	Pathogenic
3897717	NM_003054.6(SLC18A2):c.700+2T>G	Likely pathogenic
402145	NM_003054.6(SLC18A2):c.711del (p.Phe238fs)	Likely pathogenic
4077515	NM_003054.6(SLC18A2):c.464+2T>C	Likely pathogenic
4278092	NM_003054.6(SLC18A2):c.1184T>C (p.Ile395Thr)	Likely pathogenic
520811	NM_003054.6(SLC18A2):c.895G>C (p.Gly299Arg)	Likely pathogenic
548130	NM_003054.6(SLC18A2):c.1160C>T (p.Pro387Leu)	Likely pathogenic

SpliceAI

2533 predictions. Top by Δscore:

Variant	Effect	Δscore
10:117241217:CGAGG:C	donor_loss	1.0000
10:117241218:GAGGT:G	donor_loss	1.0000
10:117241219:AGGT:A	donor_loss	1.0000
10:117241220:GGTAA:G	donor_loss	1.0000
10:117241222:T:G	donor_loss	1.0000
10:117241678:GCGGA:G	acceptor_gain	1.0000
10:117254498:GTGG:G	donor_gain	1.0000
10:117255275:A:AG	acceptor_gain	1.0000
10:117255276:G:GG	acceptor_gain	1.0000
10:117255595:A:AG	acceptor_gain	1.0000
10:117255596:G:GG	acceptor_gain	1.0000
10:117255596:GA:G	acceptor_gain	1.0000
10:117257791:TTACA:T	acceptor_loss	1.0000
10:117257792:TACAG:T	acceptor_loss	1.0000
10:117257793:ACAGG:A	acceptor_loss	1.0000
10:117257794:CAGG:C	acceptor_loss	1.0000
10:117257795:A:T	acceptor_loss	1.0000
10:117257888:GCTGG:G	donor_gain	1.0000
10:117257889:C:G	donor_gain	1.0000
10:117257891:GG:G	donor_gain	1.0000
10:117257892:GG:G	donor_gain	1.0000
10:117257893:G:GG	donor_gain	1.0000
10:117257893:GT:G	donor_loss	1.0000
10:117257894:TAA:T	donor_loss	1.0000
10:117267734:TTGGT:T	donor_loss	1.0000
10:117267735:TGGTA:T	donor_loss	1.0000
10:117267737:G:GC	donor_loss	1.0000
10:117267737:G:GG	donor_gain	1.0000
10:117267738:TAAGT:T	donor_loss	1.0000
10:117270058:T:TA	acceptor_gain	1.0000

AlphaMissense

3375 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:117270178:G:A	G432R	1.000
10:117270178:G:C	G432R	1.000
10:117270178:G:T	G432W	1.000
10:117254101:G:C	G193R	0.999
10:117255294:A:C	S240R	0.999
10:117255296:T:A	S240R	0.999
10:117255296:T:G	S240R	0.999
10:117257827:C:A	A309D	0.999
10:117257845:T:C	L315P	0.999
10:117257892:G:C	G331R	0.999
10:117266753:A:C	S338R	0.999
10:117266755:T:A	S338R	0.999
10:117266755:T:G	S338R	0.999
10:117267003:G:A	G364R	0.999
10:117267003:G:C	G364R	0.999
10:117267701:T:C	L384P	0.999
10:117270110:T:C	L409P	0.999
10:117270179:G:A	G432E	0.999
10:117270185:C:A	A434D	0.999
10:117270190:G:C	G436R	0.999
10:117270330:G:A	G436D	0.999
10:117270392:G:A	G457R	0.999
10:117270392:G:C	G457R	0.999
10:117270393:G:A	G457E	0.999
10:117241790:G:C	D33H	0.998
10:117241791:A:C	D33A	0.998
10:117241791:A:T	D33V	0.998
10:117243974:C:A	P42H	0.998
10:117244256:C:A	A136D	0.998
10:117244262:A:T	K138I	0.998

dbSNP variants (sampled 300 via entrez): RS1000043662 (10:117263980 T>C), RS1000062291 (10:117249125 G>A), RS1000118236 (10:117254999 T>C), RS1000137074 (10:117263222 C>G,T), RS1000200381 (10:117273035 CT>C,CTTT), RS1000237530 (10:117240880 C>G), RS1000270062 (10:117241114 G>T), RS1000300082 (10:117252989 A>G), RS1000507015 (10:117244624 C>T), RS1000539001 (10:117244370 T>G), RS1000542898 (10:117258027 A>G), RS1000584640 (10:117242286 G>T), RS1000655961 (10:117272655 T>C), RS1000687869 (10:117279361 C>G), RS1000825214 (10:117278952 C>G,T)

Disease associations

OMIM: gene MIM:193001 | disease phenotypes: MIM:618049

GenCC curated gene-disease

Disease	Classification	Inheritance
parkinsonism-dystonia, infantile, 2	Strong	Autosomal recessive
brain dopamine-serotonin vesicular transport disease	Strong	Autosomal recessive
schizophrenia	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
brain dopamine-serotonin vesicular transport disease	Definitive	AR

Mondo (3): brain dopamine-serotonin vesicular transport disease (MONDO:0018130), (MONDO:0054836), schizophrenia (MONDO:0005090)

Orphanet (1): Brain dopamine-serotonin vesicular transport disease (Orphanet:352649)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000338	Hypomimic face
HP:0000496	Abnormality of eye movement
HP:0000508	Ptosis
HP:0000975	Hyperhidrosis
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001285	Spastic tetraparesis
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001611	Hypernasal speech
HP:0001760	Abnormal foot morphology
HP:0002075	Dysdiadochokinesis
HP:0002310	Orofacial dyskinesia
HP:0002311	Incoordination
HP:0002360	Sleep disturbance
HP:0002362	Shuffling gait
HP:0002421	Poor head control
HP:0002451	Limb dystonia
HP:0002597	Abnormality of the vasculature
HP:0003593	Infantile onset
HP:0005484	Secondary microcephaly

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005951_66	Body mass index	4.000000e-08
GCST010548_3	Retinopathy x type 2 diabetes interaction	2.000000e-08
GCST012020_25	Serum metabolite levels	6.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1893 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 548,785 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL117785	TETRABENAZINE	4	9,645
CHEMBL51	KETANSERIN	4	20,018
CHEMBL772	RESERPINE	4	330,645
CHEMBL39	SEROTONIN	3	186,160
CHEMBL122270	LOBELINE	2	2,266
CHEMBL579217	FLORBENAZINE	2	51

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs363225	Efficacy	3	bupropion	Major Depressive Disorder
rs363226	Efficacy	3	bupropion	Major Depressive Disorder
rs363341	Toxicity	3	antipsychotics	Psychotic Disorder

PharmGKB variants

12 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs14240	PDZD8, SLC18A2		0.00	0
rs363224	SLC18A2		0.00	0
rs363343	SLC18A2		0.00	0
rs363371	SLC18A2		0.00	0
rs363390	SLC18A2		0.00	0
rs929493	SLC18A2		0.00	0
rs363341	SLC18A2	3	3.00	1	antipsychotics
rs363225	SLC18A2	3	2.75	1	bupropion
rs363226	SLC18A2	3	2.25	1	bupropion
rs363338	SLC18A2		0.00	0
rs363334	SLC18A2		0.00	0
rs363332	SLC18A2		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC18 family of vesicular amine transporters

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
[3H]TBZOH	Inhibition	8.2	pKd
[125I]iodovinyl-TBZ	Inhibition	8.1	pKd
reserpine	Inhibition	7.9	pKi
tetrabenazine	Inhibition	7.0	pKi
valbenazine	Inhibition	6.73	pKi
ketanserin	Inhibition	6.3	pKi

Binding affinities (BindingDB)

1 measured of 2 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[[(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl]methoxycarbonylamino]bicyclo[2.2.1]heptane-2-carboxylic acid	KI	260 nM	US-11053242: [9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11BH-pyrido-[2,1-a]isoquinolin-2-yl]methanol and compounds, compositions and methods relating thereto

ChEMBL bioactivities

148 potent at pChembl≥5 of 149 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	Ki	0.1	nM	FLORBENAZINE
8.59	Ki	2.6	nM	DIHYDROTETRABENAZINE
8.28	Ki	5.26	nM	RESERPINE
8.28	Ki	5.2	nM	CHEMBL5943183
8.10	Kd	8	nM	RESERPINE
7.88	IC50	13.2	nM	RESERPINE
7.81	IC50	15.5	nM	RESERPINE
7.80	IC50	16	nM	CHEMBL4205254
7.71	IC50	19.7	nM	CHEMBL4207658
7.70	IC50	19.8	nM	TETRABENAZINE
7.55	IC50	28.1	nM	CHEMBL4206824
7.54	Ki	29	nM	CHEMBL5723375
7.41	IC50	39.4	nM	CHEMBL4202787
7.29	IC50	51.1	nM	CHEMBL4205254
7.21	Ki	62	nM	CHEMBL4205254
7.19	Ki	64	nM	CHEMBL213814
7.16	Ki	70	nM	CHEMBL4207658
7.16	Ki	70	nM	CHEMBL4206824
7.15	Kd	71	nM	CHEMBL4206824
7.13	Ki	74	nM	CHEMBL4202787
7.11	Ki	77	nM	KETANSERIN
7.08	Ki	83	nM	CHEMBL213814
7.07	IC50	85.5	nM	CHEMBL4214975
7.03	Kd	93	nM	CHEMBL4207838
7.03	Kd	93	nM	CHEMBL4205254
7.00	IC50	101	nM	CHEMBL4208250
6.90	IC50	125	nM	CHEMBL4208779
6.85	IC50	142	nM	CHEMBL4213176
6.82	Ki	152	nM	CHEMBL4206824
6.81	IC50	154	nM	CHEMBL213814
6.79	Ki	161	nM	CHEMBL4202787
6.75	Ki	176	nM	CHEMBL4214975
6.75	Ki	179	nM	CHEMBL4205254
6.75	IC50	180	nM	KETANSERIN
6.67	IC50	213	nM	MRK-560
6.58	Ki	260	nM	CHEMBL5999830
6.58	Ki	260	nM	CHEMBL5742591
6.58	Ki	260	nM	CHEMBL5903981
6.58	Ki	260	nM	CHEMBL6023986
6.58	Ki	260	nM	CHEMBL5970211
6.58	Ki	260	nM	CHEMBL5785786
6.58	Ki	260	nM	CHEMBL5963352
6.58	Ki	260	nM	CHEMBL5882789
6.58	Ki	260	nM	CHEMBL5835869
6.58	Ki	260	nM	CHEMBL5851297
6.58	Ki	260	nM	CHEMBL5923135
6.58	Ki	260	nM	CHEMBL6042844
6.58	Ki	260	nM	CHEMBL5855847
6.58	Ki	260	nM	CHEMBL6059797
6.58	Ki	260	nM	CHEMBL6006670

PubChem BioAssay actives

70 with measured affinity, of 112 total; 28 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R,3R,11bR)-9-(3-fluoropropoxy)-10-methoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-ol	446982: Binding affinity to VMAT2	ki	0.0001	uM
Reserpine	1387446: Displacement of [3H]reserpine from human VMAT2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	0.0053	uM
ethyl 1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-(4-fluorophenyl)piperidine-3-carboxylate	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	0.0160	uM
ethyl (3S,4S)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-phenylpiperidine-3-carboxylate	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	0.0197	uM
9,10-dimethoxy-3-(2-methylpropyl)-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-ol	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	0.0281	uM
ethyl (3S,4S)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-(4-fluorophenyl)piperidine-3-carboxylate	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	0.0394	uM
2-ethyl-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizin-2-ol	1387447: Displacement of [3H]DHTB from human VMAT2 expressed in HEK293 cell membranes incubated for 90 mins by microbeta scintillation counting method	ki	0.0640	uM
3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-1H-quinazoline-2,4-dione	1387447: Displacement of [3H]DHTB from human VMAT2 expressed in HEK293 cell membranes incubated for 90 mins by microbeta scintillation counting method	ki	0.0770	uM
ethyl (3S,4R)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-(4-fluorophenyl)piperidine-3-carboxylate	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	0.0855	uM
1,2-ditritioethyl (3R,4R)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-(4-fluorophenyl)piperidine-3-carboxylate	1387453: Binding affinity to human VMAT2 expressed in HEK293 cell membranes by scintillation counting method based saturation binding assay	kd	0.0930	uM
ethyl (3S,4S)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-thiophen-2-ylpiperidine-3-carboxylate	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	0.1010	uM
ethyl (3S,4S)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperidine-3-carboxylate	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	0.1250	uM
ethyl (3S,4S)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]piperidine-3-carboxylate	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	0.1420	uM
ethyl (3S,4S)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-(4-methylphenyl)piperidine-3-carboxylate	1387454: Displacement of 3H-syn-Ethyl 1-(2-(2,4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate from human VMAT2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	0.4520	uM
(2S,6R)-1-methyl-2,6-bis(2-naphthalen-1-ylethyl)piperidine	459752: Binding affinity to VMAT2 receptor	ki	0.6300	uM
ethyl (3S,4S)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylate	1387454: Displacement of 3H-syn-Ethyl 1-(2-(2,4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate from human VMAT2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	0.7200	uM
(2R,6S)-1-methyl-2,6-bis(2-phenylethyl)piperidine	459752: Binding affinity to VMAT2 receptor	ki	0.9700	uM
Serotonin	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	1.4300	uM
ethyl (3S,4S)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-(4-ethoxycarbonylphenyl)piperidine-3-carboxylate	1387454: Displacement of 3H-syn-Ethyl 1-(2-(2,4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate from human VMAT2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	1.6600	uM
N-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]-8-(2-methyl-3-pyridinyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine	1906750: Inhibition of vesicular monoamine transporter 2 (unknown origin)	ic50	1.8000	uM
2-[(2R,6S)-6-[(2S)-2-hydroxy-2-phenylethyl]-1-methylpiperidin-2-yl]-1-phenylethanone	1387446: Displacement of [3H]reserpine from human VMAT2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	1.8400	uM
ethyl (3S,4S)-4-[4-(dimethylamino)phenyl]-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]piperidine-3-carboxylate	1387454: Displacement of 3H-syn-Ethyl 1-(2-(2,4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate from human VMAT2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	1.9600	uM
N-methyl-1-phenylpropan-2-amine	1387455: Inhibition of human VMAT2 expressed in HEK293 cell membranes assessed as reduction in [3H[-5HT uptake pre-incubated for 10 mins before [3H[-5HT addition and measured after 6 mins	ic50	3.6200	uM
ethyl (3S,4S)-1-[2-(2,4-dioxo-1H-quinazolin-3-yl)ethyl]-4-(4-phenylphenyl)piperidine-3-carboxylate	1387454: Displacement of 3H-syn-Ethyl 1-(2-(2,4-Dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate from human VMAT2 expressed in HEK293 cell membranes incubated for 60 mins by scintillation counting method	ki	3.7700	uM
(1R)-2-[(2R,6S)-1-methyl-6-[(E)-2-phenylethenyl]piperidin-2-yl]-1-phenylethanol	459752: Binding affinity to VMAT2 receptor	ki	5.1600	uM
2-[2-[[3-[(3S)-3-amino-2,3-dihydro-1-benzofuran-5-yl]-5-propan-2-ylphenyl]methoxy]phenyl]acetic acid	1660743: Inhibition of VMAT2 (unknown origin)	ic50	5.2000	uM
(1S)-2-[(2S,6R)-1-methyl-6-[(E)-2-phenylethenyl]piperidin-2-yl]-1-phenylethanol	459752: Binding affinity to VMAT2 receptor	ki	6.0600	uM
2-[4-chloro-12-(2-hydroxypropan-2-yl)-9-oxo-5-thia-1,10,11-triazatricyclo[6.4.0.02,6]dodeca-2(6),3,7,11-tetraen-10-yl]-N-[(3R)-1-methylpiperidin-3-yl]acetamide	2098068: Inhibition of VMAT-2 (unknown origin)	ic50	6.5000	uM

CTD chemical–gene interactions

52 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	6
Dopamine	increases uptake, affects binding, decreases activity, decreases reaction	4
Reserpine	affects binding, decreases reaction, increases uptake, decreases activity, decreases response to substance	4
Methamphetamine	decreases activity, decreases expression	3
Tetrabenazine	affects binding, decreases activity	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Norepinephrine	affects binding, decreases activity	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Serotonin	affects binding, affects uptake	2
GSK-J4	increases expression	1
para-methyl-4-methylaminorex	increases uptake, decreases reaction	1
valbenazine	decreases activity	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation, affects cotreatment	1
trichostatin A	increases expression	1
aroclor 1260	decreases activity	1
aflatoxin B2	increases methylation	1
vanoxerine	affects binding	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	decreases activity	1
CGP 52608	increases reaction, affects binding	1
pyrazolanthrone	decreases activity, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	increases expression, decreases expression, affects cotreatment	1
jinfukang	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	decreases expression	1

ChEMBL screening assays

28 unique, capped per target: 26 binding, 1 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1044344	Binding	Binding affinity to VMAT2	Synthesis and evaluation of 2-amino-dihydrotetrabenzine derivatives as probes for imaging vesicular monoamine transporter-2. — Bioorg Med Chem Lett
CHEMBL4668878	ADMET	Inhibition of VMAT2 (unknown origin) at 10 uM relative to control	Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases. — J Med Chem
CHEMBL5209602	Functional	Substrate uptake and inhibition of the Vesicular Amine Transporter 2 (VMAT2, SLC18A2) as assessed by uptake of a fluorescent substrate (FFN206) in HEK-293 JumpIN-SLC18A2 cells (PubChem AID: 1794817)	FFN206 based assay for SLC18A2 using HEK-293 SLC18A2 OE cells

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TL74	HAP1 SLC18A2 (-) 1	Cancer cell line	Male
CVCL_TL75	HAP1 SLC18A2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety