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FLASH GENE
Symbol SLC6A3 contributors: mct - updated : 20-04-2020
HGNC name solute carrier family 6 (neurotransmitter transporter, dopamine), member 3
HGNC id 11049
Corresponding disease
ADHD attention deficit hyperactivity disorder
PKDYS1 Parkinsonism-dystonia, infantile, 1
Location 5p15.3      Physical location : 1.392.904 - 1.445.543
Synonym name
  • Dopamine active transporter gene
    • Synonym symbol(s) DAT1, DAT, PKDYS, PKDYS1
    DNA
    TYPE functioning gene
    STRUCTURE 52.64 kb     15 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   enhancer   silencer
    motif repetitive sequence   other
    text structure
  • transcriptional regulatory element and VNTR (in the 3' and 5' ) for the mRNA stability, neural-specific silencer
  • a variable number of tandem repeat (VNTR) polymorphism in the 15th exon, a region encoding the transcript 3prime UTR (Dreher 2009)
  • Intron 1 contains a 121-bp fragment that down-regulated both SV40 and SLC6A3 promoter activities
  • carries a 5' distal 5-kb super enhancer (5KSE) which upregulated the promoter by 5-fold, that is able to prevent 3' downstream variable number tandem repeats (3'VNTRs) from silencing the promoter
    • MAPPING cloned Y linked Y status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    15 - 3952 68 620 - 2010 20700532
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Nervousbrainmidbrainsubstantia nigra  
     brainlimbic systemhippocampus  
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatum   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousdopaminergic neuron
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N- and C-terminal ends facing the cytoplasmic side
    • and importance of the N-terminus in the transport of SLC6A3 to striatal terminals
  • 12 transmembrane segments (12TM)
  • a C-terminal PDZ (PSD-95/Discs-large/ZO-1) domain-binding sequence believed to bind synaptic scaffolding proteins, critical for synaptic distribution of dopamine transporter and thereby for proper maintenance of dopamine homoeostasis
    • conjugated GlycoP
    mono polymer homomer , oligo
    HOMOLOGY
    interspecies homolog to murine Slc6a3 (93.7pc)
    homolog to rattus Slc6a3 (93.7pc)
    Homologene
    FAMILY
  • sodium:neurotransmitter symporter (SNF) family
  • Na+- and Cl--dependent neurotransmitter transporter family SLC6
    • CATEGORY transport carrier
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm
    text
  • centrosomal aggregates and fragmentation of Golgi are 2 closely related processes that could result in the disruption of the vesicular transport of SLC6A3 toward the plasma membrane in a model of dopaminergic neuronal degeneration
  • accumulate in filopodia in neurons and non-neuronal cells, and outward-facing (OF) conformation is required for the efficient targeting of SLC6A3 to, and accumulation in, filopodia
    • basic FUNCTION
  • mediating the active reuptake of dopamine from the synapse
  • is a principal regulator of dopaminergic neurotransmission
  • SLC6A2, SLC6A3 control neurotransmitter levels within the synaptic cleft and are the site of action for amphetamine (AMPH) and cocaine
  • MAOA, SLC6A2, SLC6A3 may play important roles in regulating maternal monoamine neurotransmitters transferred across the placenta to the fetus
  • SLC6A3, SLC6A2, SLC6A4 facilitate the homeostatic balance of neurotransmitters in the synaptic cleft and thus, play a fundamental role in regulating neuronal activity
  • plays a major role in modulating dopaminergic neurotransmission by controlling the levels of dopamine in the synaptic space
  • plays an important role in the cessation of dopaminergic neurotransmission and in the maintenance of extracellular dopamine homeostasis
  • putative involvement of SLC6A3 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder
  • TH and dopamine transporters (SLC6A3) regulate dopamine (DA) neurotransmission at the biosynthesis and reuptake steps, respectively
  • mediates uptake of dopamine into presynaptic terminals
  • SLC6A3 target of psychostimulant drugs, is the key protein that regulates spatial and temporal activity of Dopamine (DA) in the synaptic cleft via the rapid reuptake of DA into the presynaptic terminal
  • age-related reduction in striatal SLC6A3 density predicted memory decline, suggesting that a relation between striatal functions and memory decline in aging is multifaceted
  • is involved in the pathophysiology of anxiety and depression
  • regulates the level of the neurotransmitter dopamine (DA) in the synaptic cleft and recycles DA for storage in the presynaptic vesicular pool
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • forms stable dimers in the live cell plasma membrane in a phosphatidylinositol 4,5-bisphosphate-independent manner
    • INTERACTION
    DNA
    RNA
    small molecule
  • carries an endogenous binding site for Zn(2+), and Zn(2+) dissociated more rapidly from the inward- than from the outward-facing state of SLC6A3
    • protein
  • interacting with PRKCABP and TGFB1I1
  • interacting with members of HESR family (the inhibitory effects of HEY1, HEY2, HEYL on SLC6A3 reporter gene expression differed depending on the number of repeats in the VNTR domain)
  • SLC6A3 is a direct target of LMX1A, emphasizing a novel role of LMX1A as one of regulators of mature midbrain dopaminergic neurotransmitter phenotypes
  • PARK7 may also play a role in regulating dopamine levels by modifying SLC6A3 activity
  • SLC6A3 expression affects TH expression and phosphorylation largely in Dopamine (DA) terminal field compartments
  • SNAPIN, a SNARE-associated protein implicated in synaptic transmission, is a new binding partner of the carboxyl terminal of SLC6A3
  • SNAPIN/SLC6A3 interaction represents a direct link between exocytotic and reuptake mechanisms and is a potential target for DA (dopamine) transmission modulation
  • NR4A2 is an orphan transcription factor that influences the expression of several key proteins of dopaminergic (DA) neurons, including tyrosine hydroxylase (TH), dopamine transporter (SLC6A3), and vesicular monoamine transporter (SLC18A1)
    • cell & other
    REGULATION
    Other
  • the negative charge provided either by chloride or by the transporter itself is required during binding and translocation of the neurotransmitter
    • may be regulated via either its promoter or the variable number tandem repeats independently by specific signaling pathways and in a haplotype-dependent manner
    ASSOCIATED DISORDERS
    corresponding disease(s) ADHD , PKDYS1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   amplification    
    in early stages of non-small cell lung cancer (Kang 2008)
    constitutional   deletion    
    promoted a previously unobserved conformation of the intracellular gate of the transporter, likely representing the rate-limiting step of the transport process
    tumoral     --over  
    in Clear Cell Renal Cell Carcinoma
    Susceptibility
  • to attention deficit hyperactivity disorder with preferential transmission of paternal alleles
  • to bipolar affective disorder, psychiatric disorders of children and cigarette smoking, alcoholism, cocaine-induced paranoia
  • to migraine with aura
  • to hypertension
    • Variant & Polymorphism repeat
  • Int8 VNTR is associated with cocaine dependence
  • 10 repeat allele of the 3' UTR VNTR show a significant main effect on relative SLC6A3 expression
  • SLC6A3 40bo VNTR showed an association with the peak tic severity in Tourette Syndrome (patients with one copy of the 9-repeat allele had significantly more severe symptoms than individuals with the homozygous 10/10 genotype)
  • SLC6A3 genotype influence these attentional/cognitive functions which deficits are not the key symptoms in ADHD
  • SLC6A3-MS8 (rs3836790), having an 8/6-repeat allele, which was only detected in hypertensive cases, was associated with hypertension
    • Candidate gene candidate gene for Parkinson's disease (PD) on the basis of its critical role in dopaminergic neurotransmission
    Marker
  • potential epigenetic biomarker with value in the early diagnosis and management of neurodevelopmental diseases in newborns
  • novel biomarker that is highly specific for ccRCC (Clear Cell Renal Cell Carcinoma)
    • Therapy target
  • target of psychomotor stimulants such as amphetamines or cocaine
  • is a target for psychoactive drugs (Dreher 2009)
    • SystemTypeDisorderPubmed
    psychiatry  
    targeting SLC6A3 activity might be a very attractive approach to tackle affective disorders
    ANIMAL & CELL MODELS
  • mice lacking SLC6A3 protein have elevated dopaminergic tone and are hyperactive, with a decrease in locomotion in response to psychostimulants
  • SLC6A3 null mice with pharmacologic inhibition of tyrosine hydroxylase demonstrated severe akinesia, rigidity, tremor and psotis similar to behaviors observed in patients with Parkinson Disease. L-dopa temporarily restored locomotion and amphetamines deriatives showed effectiveness in reducing motor abnormalities