|Solute carrier family 6 (neurotransmitter transporter), member 4|
|Symbols||; 5-HTT; 5-HTTLPR; 5HTT; HTT; OCD1; SERT; SERT1; hSERT|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
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 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, 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. Drugs that reduce the binding of serotonin to transporters (selective serotonin reuptake inhibitors, or SSRIs) 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.
- compound 4b: Ki = 17 pM; 710-fold and 11,100-fold selective over DAT and NET
- compound (+)-12a: Ki = 180 pM at hSERT; >1000-fold selective over hDAT, hNET, 5-HT1A, and 5-HT6. Isosteres
- 3-cis-(3-Aminocyclopentyl)indole 8a: Ki = 220 pM
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, edited by Larry et al. (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.
- Tamagnan G, Alagille D, Fu X, Kula NS, Baldessarini RJ, Innis RB, Baldwin RM (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.
- Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ (2005). "Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors". Journal of Medicinal Chemistry 48 (19): 6023–34. doi:10.1021/jm0503291. PMID 16162005.
- 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 (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.
- King HD, Meng Z, Deskus JA, Sloan CP, Gao Q, Beno BR, Kozlowski ES, Lapaglia MA, Mattson GK, Molski TF, Taber MT, Lodge NJ, Mattson RJ, Macor JE (November 2010). "Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors". Journal of Medicinal Chemistry 53 (21): 7564–72. doi:10.1021/jm100515z. PMID 20949929.
- Dahlin A, Royall J, Hohmann JG, Wang J (2009). "Expression profiling of the solute carrier gene family in the mouse brain". J. Pharmacol. Exp. Ther. 329 (2): 558–70. doi:10.1124/jpet.108.149831. PMC 2672879. PMID 19179540.
- Nakamura M, Ueno S, Sano A, Tanabe H (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". American Journal of Medical Genetics 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" (PDF). CNS spectrums 14 (9): 462–3. PMID 19890228.
- Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (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 KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR (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 12 June 2008.
- 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.