Serotonin transporter

The serotonin transporter (SERT) is a monoamine transporter protein.

This protein 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 a target of psychomotor stimulants, such as amphetamine, cocaine and MDMA, and 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. [cite web | title = Entrez Gene: SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6532| accessdate = ]

Function

It reuptakes serotonin in the synaptic cleft and terminates its function. It allows neurons, platelets, and other cells to accumulate the chemical neurotransmitter serotonin, which affects emotions and drives.

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 receptor.

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 [Cite journal
author = Marazziti D, Akiskal HS, Rossi A, Cassano GB
title = Alteration of the platelet serotonin transporter in romantic love
journal = Psychological Medicine
year = 1999
month = May
volume = 29
issue = 3
pages = 741–745
pmid = 10405096
url =
doi = 10.1017/S0033291798007946] , hypertension and generalized social phobia. [Cite journal
author = van der Wee NJ, van Veen JF, Stevens H, van Vliet IM, van Rijk PP, Westenberg HG
title = Increased Serotonin and Dopamine Transporter Binding in Psychotropic Medication–Naïve Patients with Generalized Social Anxiety Disorder Shown by 123I-β-(4-Iodophenyl)-Tropane SPECT
journal = The Journal of Nuclear Medecine
year = 2008
month = May
volume = 49
issue = 5
pages = 757–763
pmid = 18413401
doi = 10.2967/jnumed.107.045518]

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 (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.

Genetics

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.Cite journal
author = M. Nakamura, S. Ueno, A. Sano & H. Tanabe
title = The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants
journal = Molecular Psychiatry
year = 2000
volume = 5
pages = 32–38
pmid = 10673766 | doi = 10.1038/sj.mp.4000698]

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.Cite journal
author = Murphy DL, Lesch KP | title = Targeting the murine serotonin transporter: insights into human neurobiology
journal = Nature Reviews Neuroscience
volume = 9
pages = 85–96
month = February
year = 2008
pmid = 18209729 | doi = 10.1038/nrn2284] 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"). [Cite journal
author = Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP
title = Allelic variation of human serotonin transporter gene expression
journal = Journal of Neurochemistry
volume = 66
issue = 6
pages = 2621–2624
year = 1996
month = June
pmid = 8632190
doi = 10.1046/j.1471-4159.1996.66062621.x
doi_brokendate = 2008-06-21] 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. [Cite journal
author = Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR,Hamer DH, Murphy DL
doi = 10.1126/science.274.5292.1527
issue = 5292
journal = Science
month = November
title = Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region
url =
volume = 274
year = 1996
pages = 1527
pmid = 8929413 ] This polymorphism has been extensively investigated in over 300 scientific studies (as of 2006). [Cite journal
title = Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs255531
journal = Molecular Psychiatry
year = 2006
pages = 1–3
doi = 10.1038/sj.mp.4001789
author = Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL
pmid = 16402131 | volume = 274] 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.

The low-expression variant of the 5-HTTLPR polymorphism (the short version) increased risk of socalled "posthurricane" post-traumatic stress disorder (PTSD) and major depression but only under the conditions of high hurricane exposure and low social support after adjustment for sex, ancestry, and age.Similar effects were found for major depression. High-risk individuals (high hurricane exposure, the low-expression 5-HTTLPR variant, low social support) were at 4.5 times the risk of developing PTSD and major depression of low-risk individuals. [Cite journal
author = Kilpatrick DG, Koenen KC, Ruggiero KJ, Acierno R, Galea S, Resnick HS, Roitzsch J,Boyle J, Gelernter J
year = 2007
month = November
title = The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults
journal = The American Journal of Psychiatry
volume = 164
issue = 11
pages = 1693–1699
pmid = 17974934
doi = 10.1176/appi.ajp.2007.06122007]

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. [Cite journal
author = Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR
title = 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression
journal = Nature Neuroscience
volume = 8
issue = 6
month = June
year = 2005
pmid = 15880108 | doi = 10.1038/nn1463
pages = 828] In another study, people who inherited two short alleles were found to have more neurons and a larger volume in the pulvinar and limbic regions of the thalamus. Enlargement of the thalamus and reduced cortical volume provides an anatomical basis for why people who inherit the 5-HTTLPRshort/short genotype are more vulnerable to major depression, post-traumatic stress disorder, and suicide. [Young KA, Holcomb LA, Yazdani U, Bonkale W, Hicks PB and German DC. 5HTTLPR polymorphism and enlargement of the pulvinar: Unlocking the backdoor to the limbic system. "Biol Psychiatry". 2007. 61: 813-8 PMID 17083920.] In contrast, a 2008 meta-analysis found no significant overall association between the 5-HTTLPR polymorphism and autism.cite journal |journal= Am J Med Genet B Neuropsychiatr Genet |date=2008 |title= Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis |author= Huang CH, Santangelo SL |doi=10.1002/ajmg.b.30720 |pmid=18286633 |volume= 8 |pages= 828]

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). [Cite journal
author = Wendland JR, Moya PR, Kruse MR, Ren-Patterson RF, Jensen CL, Timpano KR, Murphy DL
title = A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder
journal = Human molecular genetics
volume = 17
issue = 5
pages = 717–713
year = 2008
month = March
doi = 10.1093/hmg/ddm343
pmid = 18055562
url = ]

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. [Cite journal
author = Ozaki N, Goldman D, Kaye WH, Plotnicov K, Greenberg BD, Lappalainen J, Rudnick G,Murphy DL
title = Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype
journal = Molecular Psychiatry
volume = 8
pages = 933–936
year = 2003
pmid = 14593431 | doi = 10.1038/sj.mp.4001365
url = News article:
* Cite news
author = Reuters
title = Gene Found for Obsessive-Compulsive Disorder
publisher = Mental Health E-News
date = 2003-10-27
url = http://www.nyaprs.org/Pages/View_ENews.cfm?ENewsID=2842
accessdate = 2008-01-25] [Cite journal
author = 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
title = Support for the association between the rare functional variant I425V of the serotonin transporter gene and susceptibility to obsessive compulsive disorder
journal = Molecular Psychiatry
year = 2005
volume = 10
pages = 1059–1061
pmid = 16088327 | doi = 10.1038/sj.mp.4001728
url = ] [Cite web
author = Stephen Wheless
title = "The OCD Gene" Popular Press v. Scientific Literature: Is SERT Responsible for Obsessive-Compulsive Disorder?
publisher = Davidson College
url = http://www.bio.davidson.edu/courses/genomics/2004/Wheless/SERT.html
accessdate = 2008-06-12]

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 statistical significant association with schizophrenia. [Cite journal
author = Fan JB, Sklar P
title = Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia
journal = Molecular Psychiatry
year = 2005
month = October
volume = 10
issue = 10
pages = 928–938
pmid = 15940296
doi = 10.1038/sj.mp.4001690] 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. [Cite journal
author = Anguelova M, Benkelfat C, Turecki G
title = A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders
journal = Molecular Psychiatry
year = 2003
month = June
volume = 8
issue = 6
pages = 574–591
pmid = 12851635
doi = 10.1038/sj.mp.4001328]

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. [Cite journal
author = Kazantseva AV, Gaysina DA, Faskhutdinova GG, Noskova T, Malykh SB,Khusnutdinova EK
title = 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
journal = Psychiatric Genetics
volume = 18
issue = 4
pages = 167–166
year = 2008
month = August
doi = 10.1097/YPG.0b013e328304deb8
pmid = 18628678
doi_brokendate = 2008-10-05]

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. [Cite journal
author = Houle S, Ginovart N, Hussey D, Meyer JH, Wilson AA
title = Imaging the serotonin transporter with positron emission tomography: initial human studies with [¹¹C] DAPP and [¹¹C] DASB
journal = European Journal of Nuclear Medicine and Molecular Imaging
volume = 27
issue = 11
month = October
year = 2000
pmid = 11105830 | doi = 10.1007/s002590000365
pages = 1719] 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 a iodine-123 isotope that is used for brain scanning with "single photon emission computed tomography" (SPECT). [Cite journal
author = T. Brücke, J. Kornhuber, P. Angelberger, S. Asenbaum, H. Frassine, I. Podreka
title = SPECT imaging of dopamine and serotonin transporters with [¹²³I] β-CIT. Binding kinetics in the human brain
journal = Journal of Neural Transmission
volume = 94
issue = 2
year = 1993
month = June
pages = 137–146
url =
doi = 10.1007/BF01245007] The radioligands have been used to examine whether variables such as age, gender or genotype are associated with differential serotonin transporter binding. [Cite journal
author = Brust P, Hess S, Müller U, Szabo Z
title = Neuroimaging of the Serotonin Transporter — Possibilities and Pitfalls
journal = Current Psychiatry Reviews
year = 2006
month = February
volume = 2
issue = 1
pages = 111–149
url = http://www-bmu.psychiatry.cam.ac.uk/publications/brust06neu.pdf
doi = 10.2174/157340006775101508] 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. [Cite journal
author = Takano A, Arakawa R, Hayashi M, Takahashi H, Ito H, Suhara T
title = Relationship between neuroticism personality trait and serotonin transporter binding
journal = Biological Psychiatry
volume = 62
issue = 6
month = September
year = 2007
pages = 588–592
doi = 10.1016/j.biopsych.2006.11.007
pmid = 17336939]

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. [Cite journal
author = Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR
title = 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression
journal = Nature Neuroscience
volume = 8
issue = 6
month = June
year = 2005
pmid = 15880108 | doi = 10.1038/nn1463
pages = 828]

References

Further reading

* NIH press release: [http://www.nih.gov/news/pr/aug2003/niaaa-18.htm Serotonin Transporter Gene Shown to Influence College Drinking Habits]
* Cite journal
author = Roiser JP, Cook LJ, Cooper JD, Rubinsztein DC, Sahakian BJ
title = Association of a Functional Polymorphism in the Serotonin Transporter Gene With Abnormal Emotional Processing in Ecstasy Users
journal = American Journal of Psychiatry
year = 2005
month = March
volume = 162
issue = 3
pages = 609–612
pmid = 15741482
doi = 10.1176/appi.ajp.162.3.609PBB_Further_reading
citations =
*cite journal | author=Ueno S |title=Genetic polymorphisms of serotonin and dopamine transporters in mental disorders |journal=J. Med. Invest. |volume=50 |issue= 1-2 |pages= 25–31 |year= 2003 |pmid= 12630565 |doi=
*cite journal | author=Anguelova M, Benkelfat C, Turecki G |title=A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior |journal=Mol. Psychiatry |volume=8 |issue= 7 |pages= 646–53 |year= 2004 |pmid= 12874600 |doi= 10.1038/sj.mp.4001336
*cite journal | author=Holmes A, Hariri AR |title=The serotonin transporter gene-linked polymorphism and negative emotionality: placing single gene effects in the context of genetic background and environment |journal=Genes Brain Behav. |volume=2 |issue= 6 |pages= 332–5 |year= 2004 |pmid= 14653304 |doi=10.1046/j.1601-1848.2003.00052.x
*cite journal | author=Smits KM, Smits LJ, Schouten JS, "et al." |title=Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review |journal=Mol. Psychiatry |volume=9 |issue= 5 |pages= 433–41 |year= 2004 |pmid= 15037864 |doi= 10.1038/sj.mp.4001488
*cite journal | author=Cho HJ, Meira-Lima I, Cordeiro Q, "et al." |title=Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis |journal=Mol. Psychiatry |volume=10 |issue= 8 |pages= 771–81 |year= 2005 |pmid= 15824745 |doi= 10.1038/sj.mp.4001663
*cite journal | author=Serretti A, Benedetti F, Zanardi R, Smeraldi E |title=The influence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments |journal=Prog. Neuropsychopharmacol. Biol. Psychiatry |volume=29 |issue= 6 |pages= 1074–84 |year= 2005 |pmid= 15939518 |doi= 10.1016/j.pnpbp.2005.03.013
*cite journal | author=Craig IW |title=The importance of stress and genetic variation in human aggression |journal=Bioessays |volume=29 |issue= 3 |pages= 227–36 |year= 2007 |pmid= 17295220 |doi= 10.1002/bies.20538

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