Serotonin transporter

Source: Wikipedia, the free encyclopedia.

SLC6A4
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000108576

ENSMUSG00000020838

UniProt

P31645

Q60857

RefSeq (mRNA)

NM_001045

NM_010484

RefSeq (protein)

NP_001036

NP_034614

Location (UCSC)Chr 17: 30.19 – 30.24 MbChr 11: 76.89 – 76.92 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

presynaptic neuron, in a process known as serotonin reuptake.[6]

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

sudden infant death syndrome, aggressive behavior in Alzheimer disease patients, post-traumatic stress disorder and depression-susceptibility in people experiencing emotional trauma.[8]

Mechanism of action

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

sodium-potassium adenosine triphosphatase
.

The serotonin transporter first binds a sodium ion, followed by the serotonin, 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.[9]

Function

The serotonin transporter removes serotonin from the synaptic cleft back into the synaptic

presynaptic neuron.[7]

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

romantic love,[10] hypertension and generalized social phobia.[11]

The serotonin transporter is also present in

vasoconstrictive
substance. It also serves as a signalling molecule to induce platelet aggregation.

Pharmacology

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

SLC6A4.[12][13] In December 1996, a group of researchers led by D.A. Collier of the Institute of Psychiatry, Psychology and Neuroscience, published their findings in Molecular Psychiatry, that, "5-HTTLPR-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders."[14]

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 and the tricyclic antidepressant (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.[15] However, studies on SERT showed that tricyclic antidepressants and selective serotonin reuptake inhibitors bind to the central binding site overlapping the substrate binding site.[16][17][18] 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.[19]

12a
4b

Ligands

  • DASB
  • compound 4b: Ki = 17 pM; 710-fold and 11,100-fold selective over DAT and NET[20]
  • compound (+)-12a: Ki = 180 pM at hSERT; >1000-fold selective over hDAT, hNET, 5-HT1A, and 5-HT6.[21] Isosteres[22]
  • 3-cis-(3-Aminocyclopentyl)indole 8a: Ki = 220 pM[23]
  • allosteric modulator: 3′-Methoxy-8-methyl-spiro{8-azabicyclo[3.2.1]octane-3,5′(4′H)-isoxazole} (compound 7a)[24]
  • allosteric modulator: p-Trifluoromethyl-methcathinone[25]

Genetics

Slc6a4 is expressed in median and dorsal raphe in the midbrain of the postnatal day 56 mouse.[26] Allen Brain Atlases
Chromosome 17

The gene that encodes the serotonin transporter is called solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4, see Solute carrier family). In humans the gene is found on chromosome 17 on location 17q11.1–q12.[27]

Mutations associated with the gene may result in changes in serotonin transporter function, and experiments with mice have identified more than 50 different phenotypic changes as a result of genetic variation. These phenotypic changes may, e.g., be increased

gut dysfunction.[28]
Some of the human genetic variations associated with the gene are:[28]

  • Length variation in the serotonin-transporter-gene-linked polymorphic region (5-HTTLPR)
  • single nucleotide polymorphism
    (SNP) in the 5-HTTLPR
  • rs25532 — another SNP in the 5-HTTLPR
  • STin2 — a
    variable number of tandem repeats (VNTR) in the functional intron
    2
  • G56A on the second exon
  • I425V on the ninth exon

Length variation in 5-HTTLPR

Main article: 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 (5-HTTLPR or SERTPR).[29]
The short variation has 14 repeats of a sequence while the long variation has 16 repeats.
personality traits.[30] This polymorphism has been extensively investigated in over 300 scientific studies (as of 2006).[31]
The 5-HTTLPR polymorphism may be subdivided further: One study published in 2000 found 14 allelic 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.[27]

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 in perigenual anterior cingulate cortex and amygdala for short allele carriers of the 5-HTTLPR polymorphism compared to subjects with the long/long genotype.[32]

In contrast, a 2008 meta-analysis found no significant overall association between the 5-HTTLPR polymorphism and autism.[33] 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[34] initial report in 2003[35] there were mixed results in replication in 2008,[36] and a 2009 meta-analysis was negative.[37] See 5-HTTLPR 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 (OCD).[38]

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.[39][40][41]

VNTR in STin2

Another noncoding polymorphism is a

VNTR in the second intron (STin2). In a 2005 study, it was found with three alleles
: 9, 10 and 12 repeats. A meta-analysis has found that the 12 repeat allele of the STin2 VNTR polymorphism had some minor (with odds ratio 1.24), but statistically significant, association with schizophrenia.[42] A 2008 meta-analysis found no significant overall association between the STin2 VNTR polymorphism and
autism.[33]
Furthermore, a 2003 meta-analysis of
affective disorders, major depressive disorder and bipolar disorder, 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.[43]

The polymorphism has also been related to

personality traits with a 2008 Russian study finding individuals with the STin2.10 allele having lower neuroticism scores as measured with the Eysenck Personality Inventory.[44]

Neuroimaging

The distribution of the serotonin transporter in the

β-CIT radioligand with an iodine-123 isotope that is used for brain scanning with single-photon emission computed tomography (SPECT) according to a 1993 article in the Journal of Neural Transmission.[46] The radioligands were used in 2006 to examine whether variables such as age, gender or genotype are associated with differential serotonin transporter binding.[47] Healthy subjects that have a high score of neuroticism—a personality trait in the Revised NEO Personality Inventory—were found to have more serotonin transporter binding in the thalamus in 2007.[48]

Neuroimaging and genetics

Studies on the serotonin transporter have combined neuroimaging and genetics methods, e.g., a voxel-based morphometry study found less grey matter in perigenual anterior cingulate cortex and amygdala for short allele carriers of the 5-HTTLPR polymorphism compared to subjects with the long/long genotype.[32]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000108576 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020838 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "SLC6A4 Gene (Protein Coding)".
  6. ^ "SLC6A4 - Sodium-dependent serotonin transporter - Homo sapiens (Human) - SLC6A4 gene & protein".
  7. ^
    ISBN 978-0-12-374019-9
    .
  8. ^ "Entrez Gene: SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4".
  9. ^ "Mechanism of Action of the Serotonin Transporter". web.williams.edu. Retrieved 28 December 2016.
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  41. ^ Stephen Wheless. ""The OCD Gene" Popular Press v. Scientific Literature: Is SERT Responsible for Obsessive-Compulsive Disorder?". Davidson College. Retrieved 12 June 2008.
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