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 classes work by binding to SERT and thus reducing serotonin reuptake.[7] 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, 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
cytoplasm and the concentrations of sodium and chloride ions in the extracellular fluid. In order to function properly the serotonin transporter requires the
membrane potential created by 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
boutons. Thus, it terminates the effects of serotonin and simultaneously enables its reuse by the
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.
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.
In 1995 and 1996, scientists in Europe had identified the polymorphism
5-HTTLPR, a serotonin-transporter in the gene 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]
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]
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
anxiety and
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)
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.[27] 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.[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 distribution of the serotonin transporter in the
brain may be imaged with
positron emission tomography using
radioligands called
DASB and DAPP; the first such studies on the human brain were reported in 2000.[45] 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-123isotope 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]
^Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U,
Riederer P,
Lesch KP (1995). "Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene". Journal of Neural Transmission. General Section. 102 (3): 247–54.
doi:
10.1007/BF01281159.
PMID8788073.
S2CID8474414.
^Collier DA, Stöber G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Müller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP (December 1996). "A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders". Molecular Psychiatry. 1 (6): 453–60.
PMID9154246.
^Koldsø H, Severinsen K, Tran TT, Celik L, Jensen HH, Wiborg O, Schiøtt B, Sinning S (February 2010). "The two enantiomers of citalopram bind to the human serotonin transporter in reversed orientations". Journal of the American Chemical Society. 132 (4): 1311–22.
doi:
10.1021/ja906923j.
PMID20055463.
^Dallanoce C, Canovi M, Matera C, Mennini T, De Amici M, Gobbi M, De Micheli C (November 2012). "A novel spirocyclic tropanyl-Δ²-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake". Bioorganic & Medicinal Chemistry. 20 (21): 6344–55.
doi:
10.1016/j.bmc.2012.09.004.
PMID23022052.
^Niello M, Cintulova D, Hellsberg E, Jäntsch K, Holy M, Ayatollahi LH, Cozzi NV, Freissmuth M, Sandtner W, Ecker GF, Mihovilovic MD, Sitte HH (2019). "para-Trifluoromethyl-methcathinone is an allosteric modulator of the serotonin transporter". Neuropharmacology. 161: 107615.
doi:
10.1016/j.neuropharm.2019.04.021.
PMID31028773.
S2CID128363044.
^Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP (June 1996). "Allelic variation of human serotonin transporter gene expression". Journal of Neurochemistry. 66 (6): 2621–4.
doi:
10.1046/j.1471-4159.1996.66062621.x.
PMID8632190.
S2CID42037860.
^Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL (November 1996). "Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region". Science. 274 (5292): 1527–31.
Bibcode:
1996Sci...274.1527L.
doi:
10.1126/science.274.5292.1527.
PMID8929413.
S2CID35503987.
^Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL (March 2006). "Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531". Molecular Psychiatry. 11 (3): 224–6.
doi:
10.1038/sj.mp.4001789.
PMID16402131.
S2CID26655014.
^
abPezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR (June 2005). "5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression". Nature Neuroscience. 8 (6): 828–34.
doi:
10.1038/nn1463.
PMID15880108.
S2CID1864631.
^
abHuang CH, Santangelo SL (September 2008). "Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis". American Journal of Medical Genetics Part B. 147B (6): 903–13.
doi:
10.1002/ajmg.b.30720.
PMID18286633.
S2CID9491697.
^Nierenberg AA (September 2009). "The long tale of the short arm of the promoter region for the gene that encodes the serotonin uptake protein". CNS Spectrums. 14 (9): 462–3.
doi:
10.1017/s1092852900023506.
PMID19890228.
S2CID24236284.
^Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (July 2003). "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene". Science. 301 (5631): 386–9.
Bibcode:
2003Sci...301..386C.
doi:
10.1126/science.1083968.
PMID12869766.
S2CID146500484.
^Uher R, McGuffin P (February 2008). "The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis". Molecular Psychiatry. 13 (2): 131–46.
doi:
10.1038/sj.mp.4002067.
PMID17700575.
S2CID24432263.
^Kazantseva AV, Gaysina DA, Faskhutdinova GG, Noskova T, Malykh SB, Khusnutdinova EK (August 2008). "Polymorphisms of the serotonin transporter gene (5-HTTLPR, A/G SNP in 5-HTTLPR, and STin2 VNTR) and their relation to personality traits in healthy individuals from Russia". Psychiatric Genetics. 18 (4): 167–76.
doi:
10.1097/YPG.0b013e328304deb8.
PMID18628678.
S2CID7423923.
^Houle S, Ginovart N, Hussey D, Meyer JH, Wilson AA (November 2000). "Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB". European Journal of Nuclear Medicine. 27 (11): 1719–22.
doi:
10.1007/s002590000365.
PMID11105830.
S2CID18932686.
^Brücke T, Kornhuber J, Angelberger P, Asenbaum S, Frassine H, Podreka I (1993). "SPECT imaging of dopamine and serotonin transporters with [123I]beta-CIT. Binding kinetics in the human brain". Journal of Neural Transmission. General Section. 94 (2): 137–46.
doi:
10.1007/BF01245007.
PMID8110440.
S2CID22034290.