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2.A.22.1.3
Dopamine:Na+ symporter, DAT (also takes up amphetamines in symport with Na+ which promotes intracellular Na+-dependent dopamine efflux (Khoshbouei et al., 2003)) [Inhibited by cocaine, amphetamines, neurotoxins, antidepressants and ethanol (Chen et al., 2004)]. (Zn2+ potentiates uncoupled Cl- conductance (Meinild et al., 2004)).  A conserved salt bridge between TMSs 1 and 10 constitutes an extracellular gate (Pedersen et al. 2014).  DAT is regulated by D3 dopamine receptors (Zapata et al., 2007). P25α (tubulin polymerization-promoting protein, TPPP; 094811) increases dopamine transporter localization to the plasma membrane (Fjorback et al., 2011). Mediates paraquat (an herbicide) neurotoxicity (Rappold et al., 2011).  Membrane cholesterol modulates the outward facing conformation and alters cocaine binding (Hong and Amara 2010).  Threonine 53 phosphorylation in the rat orthologue (P23977) (Serine 53 in the human transporter) regulates substrate reuptake and amphetamine-stimulated efflux (Foster et al. 2012).  DAT is enriched in filopodia and induces filopodia formation (Caltagarone et al. 2015).  Dasotraline is a novel inhibitor of dopamine and norepinephrine reuptake used for the treatment of attention-deficit/hyperactivity disorder (ADHD) (Hopkins et al. 2015). When in complex with 1-(1-benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), a psychoactive adictive agonists, DAT can exhibit conformational transitions that spontaneously isomerize the transporter into inward-facing state, similarly to that observed in dopamine-bound DAT (Sahai et al. 2016).  The cytoplasmic N- and C-terminal domains contribute to substrate and inhibitor binding (Sweeney et al. 2016). DAT can exist as a monomer or a cooperative dimer subject to allosteric regulation (Cheng et al. 2017). Cocaine binds in the S1 site to stabilize an inactive form of DAT (Krout et al. 2017). Dopamine efflux is caused by 3,4-methylenedioxypyrovalerone (MDPV) (Shekar et al. 2017).

Accession Number:Q01959
Protein Name:NTDO aka DAT aka SLC6A3 aka DAT1
Length:620
Molecular Weight:68495.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:12
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate chloride ions, Cl-, amphetamines, dopamine, Na+

Cross database links:

COG0733
Genevestigator: Q01959 Q01959
HEGENOM: HBG702834 HOG000116406
RefSeq: NP_001035.1   
Entrez Gene ID: 6531   
Pfam: PF00209   
Drugbank: Drugbank Link   
OMIM: 126455  gene
KEGG: hsa:6531    hsa:6531   

Gene Ontology

GO:0005737 C:cytoplasm
GO:0005887 C:integral to plasma membrane
GO:0005330 F:dopamine:sodium symporter activity
GO:0006836 P:neurotransmitter transport
GO:0030424 C:axon
GO:0016021 C:integral to membrane
GO:0043025 C:neuronal cell body
GO:0005886 C:plasma membrane
GO:0019717 C:synaptosome
GO:0035240 F:dopamine binding
GO:0005329 F:dopamine transmembrane transporter activity
GO:0008144 F:drug binding
GO:0021984 P:adenohypophysis development
GO:0007568 P:aging
GO:0008219 P:cell death
GO:0042416 P:dopamine biosynthetic process
GO:0042420 P:dopamine catabolic process
GO:0007595 P:lactation
GO:0007626 P:locomotory behavior
GO:0042136 P:neurotransmitter biosynthetic process
GO:0040018 P:positive regulation of multicellular organism growth
GO:0060134 P:prepulse inhibition
GO:0042053 P:regulation of dopamine metabolic process
GO:0051591 P:response to cAMP
GO:0042220 P:response to cocaine
GO:0042493 P:response to drug
GO:0045471 P:response to ethanol
GO:0010039 P:response to iron ion
GO:0035094 P:response to nicotine
GO:0007608 P:sensory perception of smell

References (28)

[1] “A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs.”  Vandenbergh D.J.et.al.   1359373
[2] “Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter.”  Giros B.et.al.   1406597
[3] “Pharmacological heterogeneity of the cloned and native human dopamine transporter: disassociation of [3H]WIN 35,428 and [3H]GBR 12,935 binding.”  Pristupa Z.B.et.al.   8302271
[4] “Structure and organization of the gene encoding human dopamine transporter.”  Kawarai T.et.al.   9300814
[5] “Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations.”  Vandenbergh D.J.et.al.   10889531
[6] “Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder.”  Greenwood T.A.et.al.   11304827
[7] “Human and mouse dopamine transporter genes: conservation of 5'-flanking sequence elements and gene structures.”  Donovan D.M.et.al.   7637582
[8] “Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age.”  Bannon M.J.et.al.   1353885
[9] “Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1.”  Torres G.E.et.al.   11343649
[10] “The multiple LIM domain-containing adaptor protein Hic-5 synaptically colocalizes and interacts with the dopamine transporter.”  Carneiro A.M.D.et.al.   12177201
[11] “Characterization of single-nucleotide polymorphisms in coding regions of human genes.”  Cargill M.et.al.   10391209
[12] “The consensus coding sequences of human breast and colorectal cancers.”  Sjoeblom T.et.al.   16959974
[13] “A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs.”  Vandenbergh D.J.et.al.   1359373
[14] “Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter.”  Giros B.et.al.   1406597
[15] “Pharmacological heterogeneity of the cloned and native human dopamine transporter: disassociation of [3H]WIN 35,428 and [3H]GBR 12,935 binding.”  Pristupa Z.B.et.al.   8302271
[16] “Structure and organization of the gene encoding human dopamine transporter.”  Kawarai T.et.al.   9300814
[17] “Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations.”  Vandenbergh D.J.et.al.   10889531
[18] “Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder.”  Greenwood T.A.et.al.   11304827
[19] “Sequence variation in the primate dopamine transporter gene and its relationship to social dominance.”  Miller-Butterworth C.M.et.al.   17934207
[20] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[21] “Human and mouse dopamine transporter genes: conservation of 5'-flanking sequence elements and gene structures.”  Donovan D.M.et.al.   7637582
[22] “Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age.”  Bannon M.J.et.al.   1353885
[23] “Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1.”  Torres G.E.et.al.   11343649
[24] “The multiple LIM domain-containing adaptor protein Hic-5 synaptically colocalizes and interacts with the dopamine transporter.”  Carneiro A.M.D.et.al.   12177201
[25] “Characterization of single-nucleotide polymorphisms in coding regions of human genes.”  Cargill M.et.al.   10391209
[26] “The consensus coding sequences of human breast and colorectal cancers.”  Sjoeblom T.et.al.   16959974
[27] “Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia.”  Kurian M.A.et.al.   19478460
[28] “A population-specific HTR2B stop codon predisposes to severe impulsivity.”  Bevilacqua L.et.al.   21179162

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FASTA formatted sequence
1:	MSKSKCSVGL MSSVVAPAKE PNAVGPKEVE LILVKEQNGV QLTSSTLTNP RQSPVEAQDR 
61:	ETWGKKIDFL LSVIGFAVDL ANVWRFPYLC YKNGGGAFLV PYLLFMVIAG MPLFYMELAL 
121:	GQFNREGAAG VWKICPILKG VGFTVILISL YVGFFYNVII AWALHYLFSS FTTELPWIHC 
181:	NNSWNSPNCS DAHPGDSSGD SSGLNDTFGT TPAAEYFERG VLHLHQSHGI DDLGPPRWQL 
241:	TACLVLVIVL LYFSLWKGVK TSGKVVWITA TMPYVVLTAL LLRGVTLPGA IDGIRAYLSV 
301:	DFYRLCEASV WIDAATQVCF SLGVGFGVLI AFSSYNKFTN NCYRDAIVTT SINSLTSFSS 
361:	GFVVFSFLGY MAQKHSVPIG DVAKDGPGLI FIIYPEAIAT LPLSSAWAVV FFIMLLTLGI 
421:	DSAMGGMESV ITGLIDEFQL LHRHRELFTL FIVLATFLLS LFCVTNGGIY VFTLLDHFAA 
481:	GTSILFGVLI EAIGVAWFYG VGQFSDDIQQ MTGQRPSLYW RLCWKLVSPC FLLFVVVVSI 
541:	VTFRPPHYGA YIFPDWANAL GWVIATSSMA MVPIYAAYKF CSLPGSFREK LAYAIAPEKD 
601:	RELVDRGEVR QFTLRHWLKV