Q60857 · SC6A4_MOUSE

  • Protein
    Sodium-dependent serotonin transporter
  • Gene
    Slc6a4
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Serotonin transporter that cotransports serotonin with one Na+ ion in exchange for one K+ ion and possibly one proton in an overall electroneutral transport cycle. Transports serotonin across the plasma membrane from the extracellular compartment to the cytosol thus limiting serotonin intercellular signaling (By similarity) (PubMed:9037532, PubMed:9547354).
Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse (PubMed:25600870, PubMed:9547354).
Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes (PubMed:27111230).
Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation (PubMed:18317590).
Mechanistically, the transport cycle starts with an outward-open conformation having Na1+ and Cl- sites occupied. The binding of a second extracellular Na2+ ion and serotonin substrate leads to structural changes to outward-occluded to inward-occluded to inward-open, where the Na2+ ion and serotonin are released into the cytosol. Binding of intracellular K+ ion induces conformational transitions to inward-occluded to outward-open and completes the cycle by releasing K+ possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1+ and Cl- ions remain bound throughout the transport cycle (By similarity) (PubMed:9037532, PubMed:9547354).
Additionally, displays serotonin-induced channel-like conductance for monovalent cations, mainly Na+ ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability (By similarity).

Miscellaneous

This protein is the target of psychomotor stimulants such as amphetamines or cocaine.

Catalytic activity

Kinetics

KM SUBSTRATE pH TEMPERATURE[C] NOTES EVIDENCE
403 nMserotonin
Vmax pH TEMPERATURE[C] NOTES EVIDENCE
1.02 pmol/min/mgfor serotonin

Features

Showing features for binding site.

TypeIDPosition(s)Description
Binding site94Na+ 1 (UniProtKB | ChEBI)
Binding site96Na+ 2 (UniProtKB | ChEBI)
Binding site97Na+ 1 (UniProtKB | ChEBI)
Binding site98Na+ 2 (UniProtKB | ChEBI)
Binding site98serotonin (UniProtKB | ChEBI)
Binding site101Na+ 2 (UniProtKB | ChEBI)
Binding site336Na+ 2 (UniProtKB | ChEBI)
Binding site368Na+ 2 (UniProtKB | ChEBI)
Binding site434Na+ 1 (UniProtKB | ChEBI)
Binding site437Na+ 1 (UniProtKB | ChEBI)
Binding site438Na+ 1 (UniProtKB | ChEBI)
Binding site439serotonin (UniProtKB | ChEBI)
Binding site494serotonin (UniProtKB | ChEBI)
Binding site495serotonin (UniProtKB | ChEBI)
Binding site556serotonin (UniProtKB | ChEBI)
Binding site559serotonin (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular Componentendomembrane system
Cellular Componentendosome membrane
Cellular Componentfocal adhesion
Cellular Componentmembrane raft
Cellular Componentneuron projection
Cellular Componentplasma membrane
Cellular Componentpostsynaptic membrane
Cellular Componentpresynaptic membrane
Cellular Componentserotonergic synapse
Cellular Componentsynapse
Molecular Functionactin filament binding
Molecular Functionantiporter activity
Molecular Functioncocaine binding
Molecular Functionidentical protein binding
Molecular Functionintegrin binding
Molecular Functionmonoamine transmembrane transporter activity
Molecular Functionmonoatomic cation channel activity
Molecular Functionneurotransmitter transmembrane transporter activity
Molecular Functionnitric-oxide synthase binding
Molecular Functionserotonin binding
Molecular Functionserotonin:sodium:chloride symporter activity
Molecular Functionsodium ion binding
Molecular Functionsyntaxin-1 binding
Biological Processamino acid transport
Biological Processbehavioral response to cocaine
Biological Processbrain morphogenesis
Biological Processcellular response to cGMP
Biological Processcellular response to retinoic acid
Biological Processcircadian rhythm
Biological Processconditioned place preference
Biological Processenteric nervous system development
Biological Processmembrane depolarization
Biological Processmemory
Biological Processmonoamine transport
Biological Processnegative regulation of cerebellar granule cell precursor proliferation
Biological Processnegative regulation of neuron differentiation
Biological Processnegative regulation of organ growth
Biological Processnegative regulation of synaptic transmission, dopaminergic
Biological Processneurotransmitter reuptake
Biological Processneurotransmitter transport
Biological Processplatelet aggregation
Biological Processpositive regulation of cell cycle
Biological Processpositive regulation of gene expression
Biological Processpositive regulation of serotonin secretion
Biological Processregulation of thalamus size
Biological Processresponse to estradiol
Biological Processresponse to hypoxia
Biological Processresponse to nutrient
Biological Processresponse to toxic substance
Biological Processresponse to xenobiotic stimulus
Biological Processserotonin transport
Biological Processserotonin uptake
Biological Processsodium ion transmembrane transport
Biological Processsperm ejaculation
Biological Processvasoconstriction

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Sodium-dependent serotonin transporter
  • Short names
    SERT
  • Alternative names
    • 5HT transporter (5HTT)
    • Solute carrier family 6 member 4

Gene names

    • Name
      Slc6a4
    • Synonyms
      Htt, Sert

Organism names

  • Taxonomic identifier
  • Strains
    • 129
    • C57BL/6J
    • BALB/cJ
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus

Accessions

  • Primary accession
    Q60857
  • Secondary accessions
    • O35241
    • Q5NCR6

Proteomes

Organism-specific databases

Subcellular Location

Cell membrane
; Multi-pass membrane protein
Endomembrane system
; Multi-pass membrane protein
Endosome membrane
; Multi-pass membrane protein
Synapse
Note: Could be part of recycling endosomes. Density of transporter molecules on the plasma membrane is itself regulated by STX1A. Density of transporter molecules on the plasma membrane is also regulated by serotonin (By similarity).
Density of transporter molecules seems to be modulated by ITGAV:ITGB3 (PubMed:29038237).

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain1-87Cytoplasmic
Transmembrane88-112Helical; Name=1
Topological domain113-115Extracellular
Transmembrane116-135Helical; Name=2
Topological domain136-160Cytoplasmic
Transmembrane161-186Helical; Name=3
Topological domain187-252Extracellular
Transmembrane253-271Helical; Name=4
Topological domain272-277Cytoplasmic
Transmembrane278-297Helical; Name=5
Topological domain298-324Extracellular
Transmembrane325-347Helical; Name=6
Topological domain348-360Cytoplasmic
Transmembrane361-380Helical; Name=7
Topological domain381-421Extracellular
Transmembrane422-443Helical; Name=8
Topological domain444-463Cytoplasmic
Transmembrane464-483Helical; Name=9
Topological domain484-494Extracellular
Transmembrane495-516Helical; Name=10
Topological domain517-538Cytoplasmic
Transmembrane539-558Helical; Name=11
Topological domain559-574Extracellular
Transmembrane575-595Helical; Name=12
Topological domain596-630Cytoplasmic

Keywords

Phenotypes & Variants

Disruption phenotype

Mutant mice are born at the expected Mendelian rate. Knockdown results in loss of serotonin uptake in synaptosomes of brainstem and cortex, abnormal barrel cortex development, enteric nervous system hyperplasia and reduced peristaltic reflexes.

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 28 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

Chemistry

PTM/Processing

Features

Showing features for chain, modified residue, disulfide bond, glycosylation.

TypeIDPosition(s)Description
ChainPRO_00002147591-630Sodium-dependent serotonin transporter
Modified residue47Phosphotyrosine
Modified residue142Phosphotyrosine
Disulfide bond200↔209
Glycosylation208N-linked (GlcNAc...) asparagine
Glycosylation217N-linked (GlcNAc...) asparagine
Modified residue276Phosphothreonine

Post-translational modification

Phosphorylation at Thr-276 increases 5-HT uptake and is required for cGMP-mediated SERT regulation.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Expressed in the lung, midbrain and brainstem regions (PubMed:9037532).
Expressed in brainstem raphe neurons (PubMed:25600870).

Induction

Expressed in a circadian manner in the midbrain with a higher level expression seen during the dark phase (at protein level).

Developmental stage

Expressed in the uncrossed ipsilateral retinal ganglion cells (iRGCs) of the peripheral ventrotemporal (VT) region segment in the retina at 16.5 dpc (PubMed:20676059).
Expressed during early postnatal brain development in neurons of brainstem and ventrobasal complex (VB) nuclei, including thalamic VB, dorso-lateral geniculate (DLG) nucleus neurons and hippocampal neurons. Expressed in the somatosensory cortex and the brainstem at postnatal day 7 (at protein level) (PubMed:25600870).

Gene expression databases

Interaction

Subunit

Monomer or homooligomer (By similarity).
Interacts (via C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly. Interacts with filamentous actin and STX1A (By similarity).
Interacts (via the N-terminus) with STX1A (via the H3 domain); this interaction regulates SLC4A6 channel conductance (By similarity).
Interacts with SEC23A, SEC24C and PATJ. Interacts with NOS1; the interaction may diminish the cell surface localization of SERT in the brain and, correspondingly, reduce serotonin reuptake (PubMed:17452640).
Interacts with TGFB1I1 (PubMed:16803896).
Interacts with ITGAV:ITGB3 (PubMed:29038237).
Interacts (via C-terminus) with ITGB3; this interaction regulates SLC6A4 trafficking (By similarity).

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntact
BINARY Q60857Nos1 Q9Z0J44EBI-15633326, EBI-397596

Protein-protein interaction databases

Chemistry

Miscellaneous

Structure

Family & Domains

Features

Showing features for region, compositional bias.

TypeIDPosition(s)Description
Region1-63Disordered
Compositional bias45-63Polar residues
Region616-624Interaction with RAB4A

Sequence similarities

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    630
  • Mass (Da)
    70,048
  • Last updated
    2011-07-27 v4
  • Checksum
    2B6ABD26E3288CD0
METTPLNSQKVLSECKDKEDCQENGVLQKGVPTPADKAGPGQISNGYSAVPSTSAGDEAPHSTPAATTTLVAEIHQGERETWGKKMDFLLSVIGYAVDLGNIWRFPYICYQNGGGAFLLPYTIMAIFGGIPLFYMELALGQYHRNGCISIWKKICPIFKGIGYAICIIAFYIASYYNTIIAWALYYLISSFTDQLPWTSCKNSWNTGNCTNYFAQDNITWTLHSTSPAEEFYLRHVLQIHQSKGLQDLGTISWQLALCIMLIFTIIYFSIWKGVKTSGKVVWVTATFPYIVLSVLLVRGATLPGAWRGVVFYLKPNWQKLLETGVWVDAAAQIFFSLGPGFGVLLAFASYNKFNNNCYQDALVTSVVNCMTSFVSGFVIFTVLGYMAEMRNEDVSEVAKDAGPSLLFITYAEAIANMPASTFFAIIFFLMLITLGLDSTFAGLEGVITAVLDEFPHIWAKRREWFVLIVVITCILGSLLTLTSGGAYVVTLLEEYATGPAVLTVALIEAVVVSWFYGITQFCSDVKEMLGFSPGWFWRICWVAISPLFLLFIICSFLMSPPQLRLFQYNYPHWSIILGYCIGTSSVICIPIYIIYRLISTPGTLKERIIKSITPETPTEIPCGDIRMNAV

Computationally mapped potential isoform sequences

There is 1 potential isoform mapped to this entry

View all
EntryEntry nameGene nameLength
Q5NCR5Q5NCR5_MOUSESlc6a4158

Sequence caution

The sequence X66119 differs from that shown. Reason: Frameshift

Features

Showing features for sequence conflict, compositional bias.

TypeIDPosition(s)Description
Sequence conflict39in Ref. 1; AAB67172, 2; CAA70092 and 4; AAA84750
Compositional bias45-63Polar residues
Sequence conflict152in Ref. 1; AAB67172 and 2; CAA70092
Sequence conflict196in Ref. 2; CAA70092
Sequence conflict415in Ref. 2; CAA70092

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AF013604
EMBL· GenBank· DDBJ
AAB67172.1
EMBL· GenBank· DDBJ
mRNA
Y08870
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08871
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08872
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08873
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08874
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08875
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08876
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08877
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08878
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08879
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
Y08880
EMBL· GenBank· DDBJ
CAA70092.1
EMBL· GenBank· DDBJ
Genomic DNA
AL603842
EMBL· GenBank· DDBJ
-Genomic DNA No translation available.
U26452
EMBL· GenBank· DDBJ
AAA84750.1
EMBL· GenBank· DDBJ
Genomic DNA
X66119
EMBL· GenBank· DDBJ
-mRNA No translation available.

Genome annotation databases

Similar Proteins

Disclaimer

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