Serotonin transporter

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 that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein that transports serotonin from the synaptic cleft to the presynaptic neuron.

This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is the target of many antidepressant medications of the SSRI and Tricyclic antidepressant classes.[1] 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.[2]

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.[1]

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 alcoholism, clinical depression, obsessive-compulsive disorder (OCD), romantic love,[3] hypertension and generalized social phobia.[4]

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.

Pharmacology

SERT spans the plasma membrane 12 times. It belongs to 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 SSRI Fluoxetine and the Tricyclic antidepressant 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.[5] However, studies on SERT showed that tricyclic antidepressants and selective serotonin reuptake inhbitors bind to the central binding site overlapping the substrate binding site.[6][7][8] 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.[9] The crystal structure of human SERT was also resolved recently[10]

12a
4b

Ligands

Genetics

Slc6a4 is expressed in median and dorsal raphe in the midbrain of the postnatal day 56 mouse.[15] 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.[16]

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.[17] Some of the human genetic variations associated with the gene are:[17]

Length variation in 5-HTTLPR

Main article: 5-HTTLPR

The promotor 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).[18] The short variation has 14 repeats of a sequence while the long variation has 16 repeats.[16] The short variation leads to less transcription for SLC6A4, and it has been found that it can partly account for anxiety-related personality traits.[19] This polymorphism has been extensively investigated in over 300 scientific studies (as of 2006).[20] 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.[16]

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 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.[21]

In contrast, a 2008 meta-analysis found no significant overall association between the 5-HTTLPR polymorphism and autism.[22] 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[23] initial report[24] there were mixed results in replication,[25] and a 2009 meta-analysis was negative.[26] 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).[27]

I425V

I425V is a rare mutation on the ninth exon. Researchers have found this genetic variation in unrelated families with OCD, and 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.[28][29][30]

VNTR in STin2

Another noncoding polymorphism is a VNTR in the second intron (STin2). It is 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.[31] A 2008 meta-analysis found no significant overall association between the STin2 VNTR polymorphism and autism.[22] Furthermore, a 2003 meta-analysis of affective disorders, major depressive disorder and bipolar disorder, found a little association to the intron 2 VNTR polymorphism, but the results of the meta-analysis depended on a large effect from one individual study.[32]

The polymorphism has also been related to personality traits with a Russian study from 2008 finding individuals with the STin2.10 allele having lower neuroticism score as measured with the Eysenck Personality Inventory.[33]

Neuroimaging

The distribution of the serotonin transporter in the brain may be imaged with positron emission tomography using radioligands called DASB and DAPP, and the first studies on the human brain were reported in 2000.[34] 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 that is used for brain scanning with single photon emission computed tomography (SPECT).[35] The radioligands have been used to examine whether variables such as age, gender or genotype are associated with differential serotonin transporter binding.[36] Healthy subjects that have a high score of neuroticism — a personality trait in the Revised NEO Personality Inventory — have been found to have more serotonin transporter binding in the thalamus.[37]

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.[21]

References

  1. 1 2 Squire, edited by Larry; et al. (2008). Fundamental neuroscience (3rd ed.). Amsterdam: Elsevier / Academic Press. p. 143. ISBN 978-0-12-374019-9.
  2. ↑ "Entrez Gene: SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4".
  3. ↑ Marazziti D, Akiskal HS, Rossi A, Cassano GB (May 1999). "Alteration of the platelet serotonin transporter in romantic love". Psychological Medicine. 29 (3): 741–5. doi:10.1017/S0033291798007946. PMID 10405096.
  4. ↑ van der Wee NJ, van Veen JF, Stevens H, van Vliet IM, van Rijk PP, Westenberg HG (May 2008). "Increased serotonin and dopamine transporter binding in psychotropic medication-naive patients with generalized social anxiety disorder shown by 123I-beta-(4-iodophenyl)-tropane SPECT". Journal of Nuclear Medicine. 49 (5): 757–63. doi:10.2967/jnumed.107.045518. PMID 18413401.
  5. ↑ Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN (September 2007). "LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake". Science. 317 (5843): 1390–3. doi:10.1126/science.1147614. PMC 3711652Freely accessible. PMID 17690258.
  6. ↑ Sinning S, Musgaard M, Jensen M, Severinsen K, Celik L, Koldsø H, Meyer T, Bols M, Jensen HH, Schiøtt B, Wiborg O (March 2010). "Binding and orientation of tricyclic antidepressants within the central substrate site of the human serotonin transporter". The Journal of Biological Chemistry. 285 (11): 8363–74. doi:10.1074/jbc.M109.045401. PMC 2832986Freely accessible. PMID 19948720.
  7. ↑ Andersen J, Taboureau O, Hansen KB, Olsen L, Egebjerg J, Strømgaard K, Kristensen AS (April 2009). "Location of the antidepressant binding site in the serotonin transporter: importance of Ser-438 in recognition of citalopram and tricyclic antidepressants". The Journal of Biological Chemistry. 284 (15): 10276–84. doi:10.1074/jbc.M806907200. PMC 2665081Freely accessible. PMID 19213730.
  8. ↑ 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. PMID 20055463.
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  13. ↑ Dalton King H, Denhart DJ, Deskus JA, Ditta JL, Epperson JR, Higgins MA, Kung JE, Marcin LR, Sloan CP, Mattson GK, Molski TF, Krause RG, Bertekap RL, Lodge NJ, Mattson RJ, Macor JE (October 2007). "Conformationally restricted homotryptamines. Part 4: Heterocyclic and naphthyl analogs of a potent selective serotonin reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters. 17 (20): 5647–51. doi:10.1016/j.bmcl.2007.07.083. PMID 17766113.
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  16. 1 2 3 Nakamura M, Ueno S, Sano A, Tanabe H (January 2000). "The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants". Molecular Psychiatry. 5 (1): 32–8. doi:10.1038/sj.mp.4000698. PMID 10673766.
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  29. ↑ Delorme R, Betancur C, Wagner M, Krebs MO, Gorwood P, Pearl P, Nygren G, Durand CM, Buhtz F, Pickering P, Melke J, Ruhrmann S, Anckarsäter H, Chabane N, Kipman A, Reck C, Millet B, Roy I, Mouren-Simeoni MC, Maier W, Råstam M, Gillberg C, Leboyer M, Bourgeron T (December 2005). "Support for the association between the rare functional variant I425V of the serotonin transporter gene and susceptibility to obsessive compulsive disorder". Molecular Psychiatry. 10 (12): 1059–61. doi:10.1038/sj.mp.4001728. PMC 2547479Freely accessible. PMID 16088327.
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