Human Gene SLC6A4 (ENST00000261707.7) Description and Page Index
  Description: Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner. (from UniProt P31645)
RefSeq Summary (NM_001045): This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, and is a member of the sodium:neurotransmitter symporter family. A repeat length polymorphism in the promoter of this gene has been shown to affect the rate of serotonin uptake. There have been conflicting results in the literature about the possible effect, if any, that this polymorphism may play in behavior and depression. [provided by RefSeq, May 2019]. Sequence Note: The RefSeq transcript and protein were derived from transcript and genomic sequence to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on alignments. There is an upstream in-frame AUG at nt 451-453 with a weak Kozak signal. This was not annotated as the translation start because it has a weak Kozak signal, while the downstream AUG at nt 577-579 has a strong Kozak signal, and is not conserved in-frame in other vertebrates except chimp. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##Evidence-Data-START## Transcript exon combination :: AK313166.1, AK308014.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support SAMEA1965299, SAMEA1968189 [ECO:0000350] ##Evidence-Data-END## ##RefSeq-Attributes-START## CDS uses downstream in-frame AUG :: upstream AUG and CDS extension is not conserved MANE Ensembl match :: ENST00000650711.1/ ENSP00000498537.1 RefSeq Select criteria :: based on single protein-coding transcript ##RefSeq-Attributes-END##
Gencode Transcript: ENST00000261707.7
Gencode Gene: ENSG00000108576.10
Transcript (Including UTRs)
   Position: hg38 chr17:30,194,321-30,235,968 Size: 41,648 Total Exon Count: 15 Strand: -
Coding Region
   Position: hg38 chr17:30,198,456-30,221,958 Size: 23,503 Coding Exon Count: 13 

Page IndexSequence and LinksUniProtKB CommentsMalaCardsCTDRNA-Seq Expression
Microarray ExpressionRNA StructureProtein StructureOther SpeciesGO AnnotationsmRNA Descriptions
PathwaysOther NamesMethods
Data last updated: 2019-09-04

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr17:30,194,321-30,235,968)mRNA (may differ from genome)Protein (630 aa)
Gene SorterGenome BrowserOther Species FASTAGene interactionsTable SchemaBioGPS
MGImyGene2neXtProtPubMedReactomeStanford SOURCE

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Sodium-dependent serotonin transporter; AltName: Full=5HT transporter; Short=5HTT; AltName: Full=Solute carrier family 6 member 4;
FUNCTION: Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.
SUBUNIT: Monomer or homooligomer (By similarity). Interacts with TGFB1I1. Interacts (via sialylated form) with MYH9. Interacts with SEC23A, SEC24C and INADL. Interacts with NOS1; the interaction may diminish the cell surface localization of SERT in the brain and, correspondingly, reduce serotonin reuptake. Interacts with filamentous actin and STX1A (By similarity). Interacts (via C- terminus) with VIM. Interacts (via C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly. Interacts with RAB4 (GTP-bound form); the interaction retains transporter molecules intracellularly.
SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. Endomembrane system; Multi-pass membrane protein. Endosome membrane; Multi-pass membrane protein. Note=Translocates from intracellular locations to the plasma membrane. Density of transporter molecules on the plasma membrane is itself regulated by serotonin.
TISSUE SPECIFICITY: Expressed in platelets (at protein level).
INDUCTION: Down-regulated when plasma serotonin is elevated.
PTM: Glycosylated; modification with sialylated N-glycans is a requirement for transporters to associate with each other and to function as homooligomeric forms (By similarity).
PTM: Phosphorylation at Thr-276 increases 5-HT uptake and is required for cGMP-mediated SERT regulation (By similarity). Phosphorylation upon PKC stimulation modifies the SERT distribution and density in the membrane, and diminishes the uptake capacity.
POLYMORPHISM: A polymorphism in the promoter region (5-HTT gene- linked polymorphic region, 5-HTTLPR) is located approximately 1 kb upstream of the transcription initiation site and is composed of 16 repeat elements. The polymorphism consists of a 44-bp insertion or deletion involving repeat elements 6 to 8. The short allele is associated with lower transcriptional efficiency of the promoter compared with the long allele. Over half of the Caucasian population has a short allele. Individuals with one or two copies of the short allele exhibit more depressive symptoms, diagnosable depression and suicidality in relation to stressful life events than individuals homozygous for the long allele.
POLYMORPHISM: The polymorphism Val-425 seems to be linked to a susceptibility to obsessive-compulsive disorder (OCD) [MIM:164230].
POLYMORPHISM: Genetic variations in SLC6A4 determine the genetic susceptibility to alcoholism [MIM:103780].
MISCELLANEOUS: This protein is the target of psychomotor stimulants such as amphetamines or cocaine.
SIMILARITY: Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A4 subfamily.
WEB RESOURCE: Name=GeneReviews; URL="";
WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="";
WEB RESOURCE: Name=Wikipedia; Note=Serotonin transporter entry; URL="";
WEB RESOURCE: Name=Protein Spotlight; Note=Love, love, love...- Issue 123 of November 2010; URL="";

-  MalaCards Disease Associations
  MalaCards Gene Search: SLC6A4
Diseases sorted by gene-association score: obsessive-compulsive disorder* (608), slc6a4-related altered drug metabolism* (100), slc6a4-related behavior disorders* (100), mood disorder (37), anxiety disorder (35), borderline personality disorder (31), personality disorder (31), alcoholic psychosis (29), premature ejaculation (25), generalized anxiety disorder (23), bipolar disorder (23), intermittent explosive disorder (23), cocaine abuse (22), retrograde amnesia (22), social phobia (20), sudden infant death syndrome (18), post-traumatic stress disorder (17), conduct disorder (17), panic disorder (17), agoraphobia (17), antisocial personality disorder (17), bulimia nervosa (16), psychotic disorder (16), irritable bowel syndrome (16), asperger syndrome (15), postpartum depression (14), pulmonary hypertension (14), eating disorder (14), endogenous depression (13), placental choriocarcinoma (13), alexithymia (13), cocaine dependence (13), major depressive disorder and accelerated response to antidepressant drug treatment (12), microscopic colitis (12), oppositional defiant disorder (12), bipolar i disorder (12), alcohol dependence (12), autistic disorder (12), opiate dependence (11), substance abuse (11), alcohol-induced mental disorder (11), mental depression (11), drug dependence (11), schizoaffective disorder (10), alcohol abuse (10), pathological gambling (9), chronic fatigue syndrome (9), brunner syndrome (9), psychosexual disorder (8), phobic disorder (8), paranoid schizophrenia (8), attention deficit-hyperactivity disorder (8), migraine with aura (8), disease of mental health (8), dyspepsia (8), atypical depressive disorder (8), trigeminal neuralgia (7), constipation (7), mitral valve disease (7), anorexia nervosa (7), gestational choriocarcinoma (7), fragile x syndrome (7), retinitis pigmentosa 20 (6), obsessive-compulsive personality disorder (6), early-onset schizophrenia (6), pervasive developmental disorder (6), bruxism (6), substance dependence (5), serotonin syndrome (5), dysthymic disorder (5), periodic limb movement disorder (5), chronic pulmonary heart disease (5), kleptomania (5), autism spectrum disorder (3), alzheimer disease (3), schizophrenia (3), migraine with or without aura 1 (3), specific developmental disorder (2), central nervous system disease (1), parkinson disease, late-onset (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 13.98 RPKM in Lung
Total median expression: 24.63 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -230.40576-0.400 Picture PostScript Text
3' UTR -1120.504135-0.271 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR000175 - Na/ntran_symport
IPR013086 - Na/ntran_symport_serotonin_N

Pfam Domains:
PF03491 - Serotonin (5-HT) neurotransmitter transporter, N-terminus
PF00209 - Sodium:neurotransmitter symporter family

ModBase Predicted Comparative 3D Structure on P31645
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
Protein SequenceProtein Sequence    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0005328 neurotransmitter:sodium symporter activity
GO:0005330 dopamine:sodium symporter activity
GO:0005335 serotonin:sodium symporter activity
GO:0005515 protein binding
GO:0008504 monoamine transmembrane transporter activity
GO:0015222 serotonin transmembrane transporter activity
GO:0015293 symporter activity
GO:0017022 myosin binding
GO:0017075 syntaxin-1 binding
GO:0017137 Rab GTPase binding
GO:0019811 cocaine binding
GO:0042803 protein homodimerization activity
GO:0046872 metal ion binding
GO:0050998 nitric-oxide synthase binding
GO:0051015 actin filament binding

Biological Process:
GO:0001666 response to hypoxia
GO:0006836 neurotransmitter transport
GO:0006837 serotonin transport
GO:0007420 brain development
GO:0007584 response to nutrient
GO:0007613 memory
GO:0007623 circadian rhythm
GO:0009636 response to toxic substance
GO:0010033 response to organic substance
GO:0010628 positive regulation of gene expression
GO:0014064 positive regulation of serotonin secretion
GO:0015844 monoamine transport
GO:0021941 negative regulation of cerebellar granule cell precursor proliferation
GO:0032227 negative regulation of synaptic transmission, dopaminergic
GO:0032355 response to estradiol
GO:0035176 social behavior
GO:0042136 neurotransmitter biosynthetic process
GO:0042310 vasoconstriction
GO:0042493 response to drug
GO:0042713 sperm ejaculation
GO:0045665 negative regulation of neuron differentiation
GO:0045787 positive regulation of cell cycle
GO:0046621 negative regulation of organ growth
GO:0048854 brain morphogenesis
GO:0051259 protein oligomerization
GO:0051260 protein homooligomerization
GO:0051583 dopamine uptake involved in synaptic transmission
GO:0051610 serotonin uptake
GO:0055085 transmembrane transport
GO:0071300 cellular response to retinoic acid
GO:0071310 cellular response to organic substance
GO:0071321 cellular response to cGMP
GO:0090067 regulation of thalamus size

Cellular Component:
GO:0005768 endosome
GO:0005829 cytosol
GO:0005886 plasma membrane
GO:0005887 integral component of plasma membrane
GO:0010008 endosome membrane
GO:0012505 endomembrane system
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0043005 neuron projection
GO:0045121 membrane raft
GO:0098793 presynapse

-  Descriptions from all associated GenBank mRNAs
  L05568 - Human Na+/Cl- dependent serotonin transporter mRNA, complete cds.
AK309538 - Homo sapiens cDNA, FLJ99579.
JD494868 - Sequence 475892 from Patent EP1572962.
JD303764 - Sequence 284788 from Patent EP1572962.
JD386939 - Sequence 367963 from Patent EP1572962.
AY902473 - Homo sapiens serotonin transporter (SLC6A4) mRNA, complete cds.
BC069484 - Homo sapiens solute carrier family 6 (neurotransmitter transporter, serotonin), member 4, mRNA (cDNA clone MGC:97139 IMAGE:7262380), complete cds.
X70697 - H.sapiens mRNA for serotonin transporter.
JD088333 - Sequence 69357 from Patent EP1572962.
JD253891 - Sequence 234915 from Patent EP1572962.
JD039073 - Sequence 20097 from Patent EP1572962.
JD111622 - Sequence 92646 from Patent EP1572962.
AK313166 - Homo sapiens cDNA, FLJ93662, highly similar to Homo sapiens solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4), mRNA.
AK308014 - Homo sapiens cDNA, FLJ97962.
JD094325 - Sequence 75349 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  Reactome (by CSHL, EBI, and GO)

Protein P31645 (Reactome details) participates in the following event(s):

R-HSA-444008 SLC6A4 co-transports 5HT, Cl-, Na+ from extracellular region to cytosol
R-HSA-380615 Serotonin clearance from the synaptic cleft
R-HSA-112311 Neurotransmitter clearance
R-HSA-112315 Transmission across Chemical Synapses
R-HSA-112316 Neuronal System

-  Other Names for This Gene
  Alternate Gene Symbols: HTT, L05568, P31645, Q5EE02, SC6A4_HUMAN, SERT, uc002hey.1, uc002hey.2, uc002hey.3, uc002hey.4, uc002hey.5, uc002hey.6
UCSC ID: uc002hey.6
RefSeq Accession: NM_001045
Protein: P31645 (aka SC6A4_HUMAN or S6A4_HUMAN)
CCDS: CCDS11256.1

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.