|Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
This is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. 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, including those of the SSRI class. 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.
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.
Neurons communicate by using chemical messages 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, hypertension and generalized social phobia.
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. Both drugs that reduce the binding of serotonin to transporters (selective serotonin reuptake inhibitors, or SSRIs) and, less often, that increase it (selective serotonin reuptake enhancers, or SSREs) are used to treat mental disorders. About half of patients with OCD are treated with SSRIs. Fluoxetine is an example of a selective serotonin reuptake inhibitor, and tianeptine is an example of a selective serotonin reuptake enhancer.
- compound (+)-12a: Ki = 180 pM at hSERT; >1000-fold selective over hDAT, hNET, 5-HT1A, and 5-HT6. Isosteres
- compound 4b: Ki = 17 pM; 710-fold and 11,100-fold selective over DAT and NET
- 3-cis-(3-Aminocyclopentyl)indole 8a: 220pM
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.
Mutations associated with the gene may result in changes in serotonin transporter function, and experiments with mice have identified more the 50 different phenotypic changes as a result of genetic variation. These phenotypic changes may, e.g., be increased anxiety and gut dysfunction. Some of the human genetic variations associated with the gene are:
- Length variation in the serotonin-transporter-gene-linked polymorphic region (5-HTTLPR)
- rs25531 — a 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 
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). The short variation has 14 repeats of a sequence while the long variation has 16 repeats. 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 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 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.
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 there were mixed results in replication, and a 2009 meta-analysis was negative. See 5-HTTLPR for more information.
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.
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. A 2008 meta-analysis found no significant overall association between the STin2 VNTR polymorphism and autism. 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.
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.
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. 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). The radioligands have been used to examine whether variables such as age, gender or genotype are associated with differential serotonin transporter binding. 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.
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.
- Squire et al., edited by Larry (2008). Fundamental neuroscience (3rd ed.). Amsterdam: Elsevier / Academic Press. p. 143. ISBN 978-0-12-374019-9.
- "Entrez Gene: SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4".
- Marazziti D, Akiskal HS, Rossi A, Cassano GB (May 1999). "Alteration of the platelet serotonin transporter in romantic love". Psychological Medicine 29 (3): 741–745. doi:10.1017/S0033291798007946. PMID 10405096.
- 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–Naïve Patients with Generalized Social Anxiety Disorder Shown by 123I-β-(4-Iodophenyl)-Tropane SPECT". The Journal of Nuclear Medicine 49 (5): 757–763. doi:10.2967/jnumed.107.045518. PMID 18413401.
- Mattson RJ, Catt JD, Denhart DJ, et al. (2005). "Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors". J. Med. Chem. 48 (19): 6023–34. doi:10.1021/jm0503291. PMID 16162005.
- Dalton King H, Denhart DJ, Deskus JA, et al. (2007). "Conformationally restricted homotryptamines. Part 4: Heterocyclic and naphthyl analogs of a potent selective serotonin reuptake inhibitor". Bioorg. Med. Chem. Lett. 17 (20): 5647–51. doi:10.1016/j.bmcl.2007.07.083. PMID 17766113.
- Tamagnan G, Alagille D, Fu X, et al. (2005). "Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency". Bioorg. Med. Chem. Lett. 15 (4): 1131–3. doi:10.1016/j.bmcl.2004.12.014. PMID 15686927.
- King HD, Meng Z, Deskus JA, et al. (November 2010). "Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors". J. Med. Chem. 53 (21): 7564–72. doi:10.1021/jm100515z. PMID 20949929.
- Dahlin, A.; Royall, J.; Hohmann, J. G.; Wang, J. (29 January 2009). "Expression Profiling of the Solute Carrier Gene Family in the Mouse Brain". Journal of Pharmacology and Experimental Therapeutics 329 (2): 558–570. doi:10.1124/jpet.108.149831. PMC 2672879. PMID 19179540.
- M. Nakamura, S. Ueno, A. Sano & H. Tanabe (2000). "The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants". Molecular Psychiatry 5 (1): 32–38. doi:10.1038/sj.mp.4000698. PMID 10673766.
- Murphy DL, Lesch KP (February 2008). "Targeting the murine serotonin transporter: insights into human neurobiology". Nature Reviews Neuroscience 9 (2): 85–96. doi:10.1038/nrn2284. PMID 18209729.
- 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): 2621–2624. doi:10.1046/j.1471-4159.1996.66062621.x. PMID 8632190.
- 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. PMID 8929413.
- Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL (2006). "Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs255531". Molecular Psychiatry 274 (3): 1–3. doi:10.1038/sj.mp.4001789. PMID 16402131.
- Pezawas 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. PMID 15880108.
- Huang CH, Santangelo SL (2008). "Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis". Am J Med Genet B Neuropsychiatr Genet 147B (6): 903–13. doi:10.1002/ajmg.b.30720. PMID 18286633.
- Nierenberg, AA (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. PMID 19890228.
- Caspi, A.; Sugden, K.; Moffitt, T. E.; Taylor, A.; Craig, I. W.; Harrington, H.; McClay, J.; Mill, J. et al. (2003). "Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene". Science 301 (5631): 386–389. Bibcode:2003Sci...301..386C. doi:10.1126/science.1083968. PMID 12869766.
- Uher, R.; McGuffin, P. (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): 131–146. doi:10.1038/sj.mp.4002067. PMID 17700575.
- Risch, N.; Herrell, R.; Lehner, T.; Liang, K.; Eaves, L.; Hoh, J.; Griem, A.; Kovacs, M. et al. (2009). "Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis". Journal of the American Medical Association 301 (23): 2462–2471. doi:10.1001/jama.2009.878. PMC 2938776. PMID 19531786.
- Wendland JR, Moya PR, Kruse MR, Ren-Patterson RF, Jensen CL, Timpano KR, Murphy DL (March 2008). "A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder". Human Molecular Genetics 17 (5): 717–713. doi:10.1093/hmg/ddm343. PMID 18055562.
- Ozaki N, Goldman D, Kaye WH, Plotnicov K, Greenberg BD, Lappalainen J, Rudnick G,Murphy DL (2003). "Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype". Molecular Psychiatry 8 (11): 933–936. doi:10.1038/sj.mp.4001365. PMID 14593431. News article:
- 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 (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): 1059–1061. doi:10.1038/sj.mp.4001728. PMC 2547479. PMID 16088327.
- Stephen Wheless. ""The OCD Gene" Popular Press v. Scientific Literature: Is SERT Responsible for Obsessive-Compulsive Disorder?". Davidson College. Retrieved 2008-06-12.
- Fan JB, Sklar P (October 2005). "Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia". Molecular Psychiatry 10 (10): 928–938. doi:10.1038/sj.mp.4001690. PMID 15940296.
- Anguelova M, Benkelfat C, Turecki G (June 2003). "A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders". Molecular Psychiatry 8 (6): 574–591. doi:10.1038/sj.mp.4001328. PMID 12851635.
- 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): 167–166. doi:10.1097/YPG.0b013e328304deb8. PMID 18628678.
- 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". Eur J Nucl Med 27 (11): 1719–22. doi:10.1007/s002590000365. PMID 11105830.
- Brücke T, Kornhuber J, Angelberger P, Asenbaum S, Frassine H, Podreka I (1993). "SPECT imaging of dopamine and serotonin transporters with [123I]β-CIT. Binding kinetics in the human brain". J. Neural Transm. Gen. Sect. 94 (2): 137–46. doi:10.1007/BF01245007. PMID 8110440.
- Brust P, Hess S, Müller U, Szabo Z (February 2006). "Neuroimaging of the Serotonin Transporter — Possibilities and Pitfalls" (PDF). Current Psychiatry Reviews 2 (1): 111–149. doi:10.2174/157340006775101508.
- Takano A, Arakawa R, Hayashi M, Takahashi H, Ito H, Suhara T (September 2007). "Relationship between neuroticism personality trait and serotonin transporter binding". Biol. Psychiatry 62 (6): 588–92. doi:10.1016/j.biopsych.2006.11.007. PMID 17336939.
Further reading 
- NIH press release: Serotonin Transporter Gene Shown to Influence College Drinking Habits
- Roiser JP, Cook LJ, Cooper JD, Rubinsztein DC, Sahakian BJ (March 2005). "Association of a Functional Polymorphism in the Serotonin Transporter Gene With Abnormal Emotional Processing in Ecstasy Users". American Journal of Psychiatry 162 (3): 609–612. doi:10.1176/appi.ajp.162.3.609. PMC 2631647. PMID 15741482.
- Ueno S (2003). "Genetic polymorphisms of serotonin and dopamine transporters in mental disorders". J. Med. Invest. 50 (1–2): 25–31. PMID 12630565.
- Anguelova M, Benkelfat C, Turecki G (2004). "A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior". Mol. Psychiatry 8 (7): 646–53. doi:10.1038/sj.mp.4001336. PMID 12874600.
- Holmes A, Hariri AR (2004). "The serotonin transporter gene-linked polymorphism and negative emotionality: placing single gene effects in the context of genetic background and environment". Genes, Brain and Behavior 2 (6): 332–5. doi:10.1046/j.1601-1848.2003.00052.x. PMID 14653304.
- Smits KM, Smits LJ, Schouten JS, et al. (2004). "Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review". Mol. Psychiatry 9 (5): 433–41. doi:10.1038/sj.mp.4001488. PMID 15037864.
- Cho HJ, Meira-Lima I, Cordeiro Q, et al. (2005). "Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis". Mol. Psychiatry 10 (8): 771–81. doi:10.1038/sj.mp.4001663. PMID 15824745.
- Serretti A, Benedetti F, Zanardi R, Smeraldi E (2005). "The influence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments". Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (6): 1074–84. doi:10.1016/j.pnpbp.2005.03.013. PMID 15939518.
- Craig IW (2007). "The importance of stress and genetic variation in human aggression". BioEssays 29 (3): 227–36. doi:10.1002/bies.20538. PMID 17295220.
- Rothman RB, Baumann MH, Blough BE, Jacobson AE, Rice KC, Partilla JS (November 2010). "Evidence for Non-Competitive Modulation of Substrate-Induced Serotonin Release". Synapse 64 (11): 862–9. doi:10.1002/syn.20804. PMC 2941209. PMID 20842720.