The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the SLC6A4

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. SERT is a type of

monoamine transporter Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible fo ...

that transports the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...

from the synaptic cleft back to the

presynaptic neuron Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous sys ...

, in a process known as serotonin reuptake. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it in a sodium-dependent manner. Many antidepressant medications of the SSRI and

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...

classes work by binding to SERT and thus reducing serotonin reuptake. It 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 and may play a role in

sudden infant death syndrome Sudden infant death syndrome (SIDS) is the sudden unexplained death of a child of less than one year of age. Diagnosis requires that the death remain unexplained even after a thorough autopsy and detailed death scene investigation. SIDS usuall ...

, aggressive behavior in Alzheimer disease patients,

post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats o ...

and depression-susceptibility in people experiencing emotional trauma.

Mechanism of action

Serotonin-reuptake transporters are dependent on both the concentration of potassium ion in the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

and the concentrations of sodium and chloride ions in the extracellular fluid. In order to function properly the serotonin transporter requires the

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...

created by the sodium-potassium adenosine triphosphatase. The serotonin transporter first binds a sodium ion, followed by the

, and then a chloride ion; it is then allowed, thanks to the membrane potential, to flip inside the cell freeing all the elements previously bound. Right after the release of the serotonin in the cytoplasm a potassium ion binds to the transporter which is now able to flip back out returning to its active state.

Function

The serotonin transporter removes serotonin from the synaptic cleft back into the synaptic boutons. Thus, it terminates the effects of serotonin and simultaneously enables its reuse by the

. Neurons communicate by using chemical messengers like serotonin between cells. The transporter protein, by recycling serotonin, regulates its concentration in a gap, or

synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...

, and thus its effects on a receiving neuron's receptors. Medical studies have shown that changes in serotonin transporter metabolism appear to be associated with many different phenomena, including

alcoholism Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomi ...

clinical depression Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

, obsessive-compulsive disorder (OCD),

romantic love Romance or romantic love is a feeling of love for, or a strong attraction towards another person, and the courtship behaviors undertaken by an individual to express those overall feelings and resultant emotions. The ''Wiley Blackwell Encyc ...

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...

and generalized social phobia. The serotonin transporter is also present in platelets; there, serotonin functions as a vasoconstrictive substance. It also serves as a signalling molecule to induce platelet aggregation. Image:Serotonin-2D-skeletal.svg,

Serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...

Pharmacology

In 1995 and 1996, scientists in Europe had identified the polymorphism

5-HTTLPR 5-HTTLPR (serotonin-transporter-linked promoter region) is a degenerate repeat polymorphic region in ''SLC6A4'', the gene that codes for the serotonin transporter. Since the polymorphism was identified in the middle of the 1990s, it has been exten ...

, a serotonin-transporter in the gene '' SLC6A4''. In December 1996, a group of researchers led by D.A. Collier of the

Institute of Psychiatry, Psychology and Neuroscience The Institute of Psychiatry, Psychology and Neuroscience (IoPPN) is a research institution dedicated to discovering what causes mental illness and diseases of the brain. In addition, its aim is to help identify new treatments for them and way ...

, published their findings in ''Molecular Psychiatry'', that, "

-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders." SERT spans the plasma membrane 12 times. It belongs to the NE, DA, SERT monoamine transporter family. Transporters are important sites for agents that treat psychiatric disorders. Drugs that reduce the binding of serotonin to transporters ( serotonin reuptake inhibitors, or SRIs) are used to treat mental disorders. The selective serotonin reuptake inhibitor (SSRI)

fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive diso ...

and the

(TCA) clomipramine are examples of serotonin reuptake inhibitors. Following the elucidation of structures of the homologous bacterial transporter, LeuT, co-crystallized with tricyclic antidepressants in the vestibule leading from the extracellular space to the central substrate site it was inferred that this binding site did also represent the binding site relevant for antidepressant binding in SERT. However, studies on SERT showed that tricyclic antidepressants and selective serotonin reuptake inhibitors bind to the central binding site overlapping the substrate binding site. The ''Drosophila'' dopamine transporter, which displays a pharmacology similar to SERT, was crystallized with tricyclic antidepressants and confirmed the earlier finding that the substrate binding site is also the antidepressant binding site. Mattson 2005

Ligands

* DASB * compound 4b: ''K''i = 17 pM; 710-fold and 11,100-fold selective over DAT and NET * compound (+)-12a: ''K''i = 180 pM at hSERT; >1000-fold selective over hDAT, hNET, 5-HT_1A, and 5-HT₆. Isosteres * 3-''cis''-(3-Aminocyclopentyl)indole 8a: ''K''i = 220 pM * allosteric modulator: 3′-Methoxy-8-methyl-spiro (compound 7a) * allosteric modulator: ''p''-Trifluoromethyl- methcathinone

Genetics

The

that encodes the serotonin transporter is called ''solute carrier family 6 (neurotransmitter transporter, serotonin), member 4'' (SLC6A4, see Solute carrier family). In

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...

s the gene is found on chromosome 17 on location 17q11.1–q12. Mutations associated with the gene may result in changes in serotonin transporter function, and experiments with

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...

have identified more than 50 different phenotypic changes as a result of genetic variation. These phenotypic changes may, e.g., be increased

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

and gut dysfunction. Some of the human genetic variations associated with the gene are: * Length variation in the serotonin-transporter-gene-linked polymorphic region (

) *

rs25531 5-HTTLPR (serotonin-transporter-linked promoter region) is a degenerate repeat polymorphic region in ''SLC6A4'', the gene that codes for the serotonin transporter. Since the polymorphism was identified in the middle of the 1990s, it has been exten ...

— a

single nucleotide polymorphism In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...

(SNP) in the 5-HTTLPR *

rs25532 RS may refer to: Businesses and organizations Sport * RS Sailing, an international designer and builder of sailboats and dinghies * Ford TeamRS, Ford Motor Company's European performance car and motorsport division * Renault Sport, performance ...

— another SNP in the 5-HTTLPR * STin2 — a

variable number of tandem repeats A variable number tandem repeat (or VNTR) is a location in a genome where a short nucleotide sequence is organized as a tandem repeat. These can be found on many chromosomes, and often show Polymorphism (biology), variations in length (number of ...

(VNTR) in the functional

intron An intron is any Nucleic acid sequence, nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of ...

2 * G56A on the second

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

* I425V on the ninth exon

Length variation in 5-HTTLPR

According to a 1996 article in ''The Journal of Neurochemistry'', the promoter region of the SLC6A4 gene contains a polymorphism with "short" and "long" repeats in a region: 5-HTT-linked polymorphic region (

or ''SERTPR''). The short variation has 14 repeats of a sequence while the long variation has 16 repeats. A second 1996 article stated that the short variation leads to less transcription for SLC6A4, and it has been found that it can partly account for anxiety-related personality traits. This polymorphism has been extensively investigated in over 300 scientific studies (as of 2006). The 5-HTTLPR polymorphism may be subdivided further: One study published in 2000 found 14

allelic An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...

variants (14-A, 14-B, 14-C, 14-D, 15, 16-A, 16-B, 16-C, 16-D, 16-E, 16-F, 19, 20 and 22) in a group of around 200 Japanese and Caucasian people. In addition to altering the expression of SERT protein and concentrations of extracellular serotonin in the brain, the 5-HTTLPR variation is associated with changes in brain structure. One 2005 study found less

grey matter Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil ( dendrites and unmyelinated axons), glial cells ( astrocytes and oligodendrocytes), synapses, and capillaries. Grey matter is ...

in perigenual

anterior cingulate cortex In the human brain, the anterior cingulate cortex (ACC) is the frontal part of the cingulate cortex that resembles a "collar" surrounding the frontal part of the corpus callosum. It consists of Brodmann areas 24, 32, and 33. It is involve ...

and

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex ver ...

for short allele carriers of the

polymorphism compared to subjects with the long/long genotype. In contrast, a 2008 meta-analysis found no significant overall association between the 5-HTTLPR polymorphism and autism. A hypothesized gene–environment interaction between the short/short allele of the 5-HTTLPR and life stress as predictor for major depression has suffered a similar fate: after an influential initial report in 2003 there were mixed results in replication in 2008, and a 2009 meta-analysis was negative. See

for more information.

rs25532

rs25532 is a SNP (C>T) close to the site of 5-HTTLPR. It has been examined in connection with

obsessive compulsive disorder Obsession may refer to: Psychology * Celebrity worship syndrome, obsessive addictive disorder to a celebrity's personal and professional life * Fixation (psychology), a persistent attachment to an object or idea * Idée fixe (psychology), a pr ...

(OCD).

I425V

I425V is a rare mutation on the ninth exon. In 2003, researchers from Japan and the US reported that they had found this genetic variation in unrelated families with OCD, and have found that it leads to faulty transporter function and regulation. A second variant in the same gene of some patients with this mutation suggests a genetic "double hit", resulting in greater biochemical effects and more severe symptoms.

VNTR in STin2

Another noncoding polymorphism is a VNTR in the second

( STin2). In a 2005 study, it was found with three

allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...

s: 9, 10 and 12 repeats. A

meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...

has found that the 12 repeat allele of the STin2 VNTR polymorphism had some minor (with

odds ratio An odds ratio (OR) is a statistic that quantifies the strength of the association between two events, A and B. The odds ratio is defined as the ratio of the odds of A in the presence of B and the odds of A in the absence of B, or equivalently (due ...

1.24), but statistically significant, association with

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

. A 2008 meta-analysis found no significant overall association between the STin2 VNTR polymorphism and

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

. Furthermore, a 2003 meta-analysis of

affective disorder Affect, in psychology, refers to the underlying experience of feeling, emotion or mood. History The modern conception of affect developed in the 19th century with Wilhelm Wundt. The word comes from the German ''Gefühl'', meaning "feeling." ...

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

and

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that last from days to weeks each. If the elevat ...

, found a minor association to the intron 2 VNTR polymorphism, but the results of the meta-analysis were dependent upon a large effect from one individual study. The polymorphism has also been related to personality traits with a 2008 Russian study finding individuals with the STin2.10 allele having lower

neuroticism In the study of psychology, neuroticism has been considered a fundamental personality trait. For example, in the Big Five approach to personality trait theory, individuals with high scores for neuroticism are more likely than average to be moody ...

scores as measured with the Eysenck Personality Inventory.

Neuroimaging

The distribution of the serotonin transporter in the

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

may be imaged with

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, ...

using

radioligand A radioligand is a radioactive biochemical substance (in particular, a ligand (biochemistry), ligand that is radioactive tracer, radiolabeled) that is used for diagnosis or for research-oriented study of the receptor (biochemistry), receptor system ...

s called DASB and DAPP; the first such studies on the human brain were reported in 2000. DASB and DAPP are not the only radioligands for the serotonin transporter. There are numerous others, with the most popular probably being the β-CIT radioligand with an iodine-123

isotope Isotopes are two or more types of atoms that have the same atomic number (number of protons in their nuclei) and position in the periodic table (and hence belong to the same chemical element), and that differ in nucleon numbers ( mass num ...

that is used for brain scanning with ''

single-photon emission computed tomography Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, ...

'' (SPECT) according to a 1993 article in the ''Journal of Neural Transmission''. The radioligands were used in 2006 to examine whether variables such as age, gender or

genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...

are associated with differential serotonin transporter binding. Healthy subjects that have a high score of

— a personality trait in the

Revised NEO Personality Inventory The Revised NEO Personality Inventory (NEO PI-R) is a personality inventory that assesses an individual on five dimensions of personality, the so-called Big Five personality traits. These traits are openness to experience, conscientiousness, ext ...

— were found to have more serotonin transporter binding in the

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...

in 2007.

Neuroimaging and genetics

Studies on the serotonin transporter have combined neuroimaging and genetics methods, e.g., a voxel-based morphometry study found less

in perigenual

and

for short allele carriers of the

polymorphism compared to subjects with the long/long genotype.

References

{{Monoamine releasing agents Membrane proteins Neurotransmitter transporters Solute carrier family Molecular neuroscience Biology of bipolar disorder Amphetamine Genes on human chromosome 17 Serotonin