SC6A3_MOUSE
ID SC6A3_MOUSE Reviewed; 619 AA.
AC Q61327; Q60719; Q9R1I2;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 27-MAY-2002, sequence version 2.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=Sodium-dependent dopamine transporter;
DE Short=DA transporter;
DE Short=DAT;
DE AltName: Full=Solute carrier family 6 member 3;
GN Name=Slc6a3; Synonyms=Dat, Dat1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SUBCELLULAR LOCATION.
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=10375632; DOI=10.1016/s0378-1119(99)00143-2;
RA Wu X., Gu H.H.;
RT "Molecular cloning of the mouse dopamine transporter and pharmacological
RT comparison with the human homologue.";
RL Gene 233:163-170(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-343.
RC STRAIN=BALB/cJ; TISSUE=Brain;
RX PubMed=7637582; DOI=10.1016/0169-328x(95)00018-n;
RA Donovan D.M., Vandenbergh D.J., Perry M.P., Bird G.S., Ingersoll R.,
RA Nanthakumar E., Uhl G.R.;
RT "Human and mouse dopamine transporter genes: conservation of 5'-flanking
RT sequence elements and gene structures.";
RL Brain Res. Mol. Brain Res. 30:327-335(1995).
RN [4]
RP INTERACTION WITH TGFB1I1.
RX PubMed=12177201; DOI=10.1523/jneurosci.22-16-07045.2002;
RA Carneiro A.M.D., Ingram S.L., Beaulieu J.-M., Sweeney A., Amara S.G.,
RA Thomas S.M., Caron M.G., Torres G.E.;
RT "The multiple LIM domain-containing adaptor protein Hic-5 synaptically
RT colocalizes and interacts with the dopamine transporter.";
RL J. Neurosci. 22:7045-7054(2002).
RN [5]
RP MUTAGENESIS OF PHE-105, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=12606774; DOI=10.1124/mol.63.3.653;
RA Wu X., Gu H.H.;
RT "Cocaine affinity decreased by mutations of aromatic residue phenylalanine
RT 105 in the transmembrane domain 2 of dopamine transporter.";
RL Mol. Pharmacol. 63:653-658(2003).
RN [6]
RP INTERACTION WITH SEPTIN4, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=17296554; DOI=10.1016/j.neuron.2007.01.019;
RA Ihara M., Yamasaki N., Hagiwara A., Tanigaki A., Kitano A., Hikawa R.,
RA Tomimoto H., Noda M., Takanashi M., Mori H., Hattori N., Miyakawa T.,
RA Kinoshita M.;
RT "Sept4, a component of presynaptic scaffold and Lewy bodies, is required
RT for the suppression of alpha-synuclein neurotoxicity.";
RL Neuron 53:519-533(2007).
RN [7]
RP INTERACTION WITH SYNGR3 AND SLC18A2, AND TISSUE SPECIFICITY.
RX PubMed=19357284; DOI=10.1523/jneurosci.4559-08.2009;
RA Egana L.A., Cuevas R.A., Baust T.B., Parra L.A., Leak R.K., Hochendoner S.,
RA Pena K., Quiroz M., Hong W.C., Dorostkar M.M., Janz R., Sitte H.H.,
RA Torres G.E.;
RT "Physical and functional interaction between the dopamine transporter and
RT the synaptic vesicle protein synaptogyrin-3.";
RL J. Neurosci. 29:4592-4604(2009).
RN [8]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=30936473; DOI=10.1038/s41556-019-0301-x;
RA Nguyen M.T., Vemaraju S., Nayak G., Odaka Y., Buhr E.D., Alonzo N.,
RA Tran U., Batie M., Upton B.A., Darvas M., Kozmik Z., Rao S., Hegde R.S.,
RA Iuvone P.M., Van Gelder R.N., Lang R.A.;
RT "An opsin 5-dopamine pathway mediates light-dependent vascular development
RT in the eye.";
RL Nat. Cell Biol. 21:420-429(2019).
CC -!- FUNCTION: Amine transporter (PubMed:10375632, PubMed:12606774).
CC Terminates the action of dopamine by its high affinity sodium-dependent
CC reuptake into presynaptic terminals (By similarity). Regulator of
CC light-dependent retinal hyaloid vessel regression, downstream of OPN5
CC signaling (PubMed:30936473). {ECO:0000250|UniProtKB:P23977,
CC ECO:0000269|PubMed:10375632, ECO:0000269|PubMed:12606774,
CC ECO:0000269|PubMed:30936473}.
CC -!- SUBUNIT: Homooligomer; disulfide-linked (By similarity). Interacts with
CC PRKCABP and TGFB1I1 (PubMed:12177201). Interacts (via N-terminus) with
CC SYNGR3 (via N-terminus) (PubMed:19357284). Interacts with SLC18A2
CC (PubMed:19357284). Interacts with TOR1A (ATP-bound); TOR1A regulates
CC SLC6A3 subcellular location. Interacts with alpha-synuclein/SNCA (By
CC similarity). Interacts with SEPTIN4 (PubMed:17296554).
CC {ECO:0000250|UniProtKB:Q01959, ECO:0000269|PubMed:12177201,
CC ECO:0000269|PubMed:17296554, ECO:0000269|PubMed:19357284}.
CC -!- INTERACTION:
CC Q61327; O55042: Snca; NbExp=5; IntAct=EBI-7839708, EBI-2310271;
CC Q61327; P37840: SNCA; Xeno; NbExp=5; IntAct=EBI-7839708, EBI-985879;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10375632,
CC ECO:0000269|PubMed:12606774}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q7K4Y6}. Cell projection, neuron projection
CC {ECO:0000250|UniProtKB:P23977}. Cell projection, axon
CC {ECO:0000269|PubMed:17296554}. Note=Localizes to neurite tips in
CC neuronal cells (By similarity). Colocalizes with SEPTIN4 at axon
CC terminals, especially at the varicosities (PubMed:17296554).
CC {ECO:0000250|UniProtKB:P23977, ECO:0000269|PubMed:17296554}.
CC -!- TISSUE SPECIFICITY: Found in the substantia nigra and ventral tegmental
CC dopamine neurons, in fibers of the medial forebrain bundle ascending
CC into the striatum, and within dense fiber networks and varicosities in
CC the dorsal and ventral striatum (at protein level) (PubMed:19357284,
CC PubMed:17296554). Lower expression in the cortex (at protein level)
CC (PubMed:19357284). Absent from the corpus callosum (PubMed:19357284).
CC Expressed throughout the retina at postnatal day 8 (PubMed:30936473).
CC {ECO:0000269|PubMed:17296554, ECO:0000269|PubMed:19357284,
CC ECO:0000269|PubMed:30936473}.
CC -!- MISCELLANEOUS: This protein is the target of psychomotor stimulants
CC such as amphetamines and cocaine.
CC -!- SIMILARITY: Belongs to the sodium:neurotransmitter symporter (SNF) (TC
CC 2.A.22) family. SLC6A3 subfamily. {ECO:0000305}.
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DR EMBL; AF109072; AAD19643.1; -; mRNA.
DR EMBL; BC054119; AAH54119.1; -; mRNA.
DR EMBL; AH003328; AAA86462.2; -; Genomic_DNA.
DR EMBL; U16265; AAC52283.1; -; mRNA.
DR CCDS; CCDS26632.1; -.
DR RefSeq; NP_034150.1; NM_010020.3.
DR AlphaFoldDB; Q61327; -.
DR SMR; Q61327; -.
DR BioGRID; 199053; 2.
DR CORUM; Q61327; -.
DR DIP; DIP-41828N; -.
DR IntAct; Q61327; 5.
DR MINT; Q61327; -.
DR STRING; 10090.ENSMUSP00000022100; -.
DR BindingDB; Q61327; -.
DR ChEMBL; CHEMBL2799; -.
DR DrugBank; DB01126; Dutasteride.
DR DrugCentral; Q61327; -.
DR GlyGen; Q61327; 4 sites.
DR iPTMnet; Q61327; -.
DR PhosphoSitePlus; Q61327; -.
DR SwissPalm; Q61327; -.
DR MaxQB; Q61327; -.
DR PaxDb; Q61327; -.
DR PRIDE; Q61327; -.
DR ProteomicsDB; 256738; -.
DR Antibodypedia; 2799; 458 antibodies from 46 providers.
DR DNASU; 13162; -.
DR Ensembl; ENSMUST00000022100; ENSMUSP00000022100; ENSMUSG00000021609.
DR GeneID; 13162; -.
DR KEGG; mmu:13162; -.
DR UCSC; uc007rdn.1; mouse.
DR CTD; 6531; -.
DR MGI; MGI:94862; Slc6a3.
DR VEuPathDB; HostDB:ENSMUSG00000021609; -.
DR eggNOG; KOG3659; Eukaryota.
DR GeneTree; ENSGT00940000161224; -.
DR HOGENOM; CLU_006855_9_0_1; -.
DR InParanoid; Q61327; -.
DR OMA; IFPEWAN; -.
DR OrthoDB; 250396at2759; -.
DR PhylomeDB; Q61327; -.
DR TreeFam; TF343812; -.
DR Reactome; R-MMU-379401; Dopamine clearance from the synaptic cleft.
DR Reactome; R-MMU-442660; Na+/Cl- dependent neurotransmitter transporters.
DR BioGRID-ORCS; 13162; 3 hits in 76 CRISPR screens.
DR ChiTaRS; Slc6a3; mouse.
DR PRO; PR:Q61327; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; Q61327; protein.
DR Bgee; ENSMUSG00000021609; Expressed in substantia nigra and 25 other tissues.
DR Genevisible; Q61327; MM.
DR GO; GO:0030424; C:axon; IDA:MGI.
DR GO; GO:0043679; C:axon terminus; IDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0098691; C:dopaminergic synapse; ISO:MGI.
DR GO; GO:0016600; C:flotillin complex; ISO:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0099055; C:integral component of postsynaptic membrane; ISO:MGI.
DR GO; GO:0099056; C:integral component of presynaptic membrane; ISO:MGI.
DR GO; GO:0016020; C:membrane; ISO:MGI.
DR GO; GO:0045121; C:membrane raft; ISO:MGI.
DR GO; GO:0043005; C:neuron projection; ISO:MGI.
DR GO; GO:0043025; C:neuronal cell body; ISO:MGI.
DR GO; GO:0032809; C:neuronal cell body membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0042734; C:presynaptic membrane; IBA:GO_Central.
DR GO; GO:0043176; F:amine binding; ISO:MGI.
DR GO; GO:0035240; F:dopamine binding; IDA:MGI.
DR GO; GO:0005330; F:dopamine:sodium symporter activity; IMP:MGI.
DR GO; GO:1901363; F:heterocyclic compound binding; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008504; F:monoamine transmembrane transporter activity; IMP:ARUK-UCL.
DR GO; GO:0005326; F:neurotransmitter transmembrane transporter activity; IMP:ARUK-UCL.
DR GO; GO:0005334; F:norepinephrine:sodium symporter activity; IBA:GO_Central.
DR GO; GO:0002020; F:protease binding; ISO:MGI.
DR GO; GO:0047485; F:protein N-terminus binding; IPI:UniProtKB.
DR GO; GO:0051721; F:protein phosphatase 2A binding; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0005102; F:signaling receptor binding; ISO:MGI.
DR GO; GO:0021984; P:adenohypophysis development; IMP:MGI.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0042416; P:dopamine biosynthetic process; IMP:MGI.
DR GO; GO:0042420; P:dopamine catabolic process; IMP:MGI.
DR GO; GO:0015872; P:dopamine transport; IMP:MGI.
DR GO; GO:0090494; P:dopamine uptake; IMP:ARUK-UCL.
DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; IBA:GO_Central.
DR GO; GO:1990384; P:hyaloid vascular plexus regression; IDA:UniProtKB.
DR GO; GO:0007595; P:lactation; IMP:MGI.
DR GO; GO:0007626; P:locomotory behavior; IMP:MGI.
DR GO; GO:0015844; P:monoamine transport; ISO:MGI.
DR GO; GO:0006836; P:neurotransmitter transport; IMP:ARUK-UCL.
DR GO; GO:0001504; P:neurotransmitter uptake; IMP:SynGO.
DR GO; GO:0015874; P:norepinephrine transport; IBA:GO_Central.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IMP:MGI.
DR GO; GO:0060134; P:prepulse inhibition; IMP:MGI.
DR GO; GO:0042053; P:regulation of dopamine metabolic process; IMP:MGI.
DR GO; GO:0051591; P:response to cAMP; ISO:MGI.
DR GO; GO:0042220; P:response to cocaine; IDA:MGI.
DR GO; GO:0045471; P:response to ethanol; ISO:MGI.
DR GO; GO:0010039; P:response to iron ion; IEA:Ensembl.
DR GO; GO:0035094; P:response to nicotine; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0007608; P:sensory perception of smell; IMP:MGI.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IBA:GO_Central.
DR InterPro; IPR000175; Na/ntran_symport.
DR InterPro; IPR002436; Na/ntran_symport_dopamine.
DR InterPro; IPR037272; SNS_sf.
DR PANTHER; PTHR11616; PTHR11616; 1.
DR Pfam; PF00209; SNF; 1.
DR PRINTS; PR01202; DOPTRANSPORT.
DR PRINTS; PR00176; NANEUSMPORT.
DR SUPFAM; SSF161070; SSF161070; 1.
DR PROSITE; PS00610; NA_NEUROTRAN_SYMP_1; 1.
DR PROSITE; PS00754; NA_NEUROTRAN_SYMP_2; 1.
DR PROSITE; PS50267; NA_NEUROTRAN_SYMP_3; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; Disulfide bond; Glycoprotein; Membrane;
KW Metal-binding; Neurotransmitter transport; Reference proteome; Sodium;
KW Symport; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..619
FT /note="Sodium-dependent dopamine transporter"
FT /id="PRO_0000214753"
FT TOPO_DOM 1..68
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 69..89
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TRANSMEM 96..116
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TRANSMEM 140..160
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 161..236
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 237..255
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TRANSMEM 264..281
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TRANSMEM 317..334
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TRANSMEM 346..367
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TRANSMEM 400..419
FT /note="Helical; Name=8"
FT /evidence="ECO:0000255"
FT TRANSMEM 446..464
FT /note="Helical; Name=9"
FT /evidence="ECO:0000255"
FT TRANSMEM 480..500
FT /note="Helical; Name=10"
FT /evidence="ECO:0000255"
FT TRANSMEM 521..540
FT /note="Helical; Name=11"
FT /evidence="ECO:0000255"
FT TRANSMEM 559..577
FT /note="Helical; Name=12"
FT /evidence="ECO:0000255"
FT TOPO_DOM 578..619
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 560..589
FT /note="Interaction with TGFB1I1"
FT /evidence="ECO:0000250"
FT BINDING 75
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT BINDING 77
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT BINDING 78
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT BINDING 82
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT BINDING 320
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT BINDING 352
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT BINDING 417
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT BINDING 420
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT BINDING 421
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT SITE 105
FT /note="Contributes to high-affinity binding to cocaine"
FT /evidence="ECO:0000269|PubMed:12606774"
FT CARBOHYD 181
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 188
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 196
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 204
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 180..189
FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6"
FT DISULFID 305
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:Q01959"
FT MUTAGEN 105
FT /note="F->A,I,L,N,Q,S,T: Very low transporter activity."
FT /evidence="ECO:0000269|PubMed:12606774"
FT MUTAGEN 105
FT /note="F->C: Reduced sensitivity to cocaine."
FT /evidence="ECO:0000269|PubMed:12606774"
FT MUTAGEN 105
FT /note="F->M: Functional transporter with 4-fold decrease in
FT cocaine sensitivity."
FT /evidence="ECO:0000269|PubMed:12606774"
FT MUTAGEN 105
FT /note="F->W,Y: Retention of transporter activity and high
FT sensitivity to cocaine."
FT /evidence="ECO:0000269|PubMed:12606774"
SQ SEQUENCE 619 AA; 68805 MW; F436137BCE461E9B CRC64;
MSKSKCSVGP MSSVVAPAKE PNAVGPREVE LILVKEQNGV QLTNSTLINP PQTPVEVQER
ETWSKKIDFL LSVIGFAVDL ANVWRFPYLC YKNGGGAFLV PYLLFMVIAG MPLFYMELAL
GQFNREGAAG VWKICPVLKG VGFTVILISF YVGFFYNVII AWALHYFFSS FTMDLPWIHC
NNTWNSPNCS DAHSSNSSDG LGLNDTFGTT PAAEYFERGV LHLHQSRGID DLGPPRWQLT
ACLVLVIVLL YFSLWKGVKT SGKVVWITAT MPYVVLTALL LRGVTLPGAM DGIRAYLSVD
FYRLCEASVW IDAATQVCFS LGVGFGVLIA FSSYNKFTNN CYRDAIITTS INSLTSFSSG
FVVFSFLGYM AQKHNVPIRD VATDGPGLIF IIYPEAIATL PLSSAWAAVF FLMLLTLGID
SAMGGMESVI TGLVDEFQLL HRHRELFTLG IVLATFLLSL FCVTNGGIYV FTLLDHFAAG
TSILFGVLIE AIGVAWFYGV QQFSDDIKQM TGQRPNLYWR LCWKLVSPCF LLYVVVVSIV
TFRPPHYGAY IFPDWANALG WIIATSSMAM VPIYATYKFC SLPGSFREKL AYAITPEKDR
QLVDRGEVRQ FTLRHWLLV
