Editing Serotonin transporter

{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Short description|Mammalian protein found in humans}}
{{Use dmy dates|date=March 2014}}
{{Infobox gene}}
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]].<ref>{{cite web | title = SLC6A4 Gene (Protein Coding) | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC6A4}}</ref> SERT is a type of [[monoamine transporter]] [[protein]] that transports the [[neurotransmitter]] [[serotonin]] from the [[synaptic cleft]] back to the [[presynaptic neuron]], in a process known as serotonin [[reuptake]].<ref>{{cite web | title = SLC6A4 - Sodium-dependent serotonin transporter - Homo sapiens (Human) - SLC6A4 gene & protein | url = https://www.uniprot.org/uniprot/P31645}}</ref>

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.<ref name="Squire2008">{{cite book | veditors = Squire L, Berg D, Bloom FE, du Lac S, Ghosh A, Spitzer NC |title=Fundamental neuroscience |year=2008 |publisher=Elsevier / Academic Press |location=Amsterdam |isbn=978-0-12-374019-9 |pages=143 |edition=3rd }}</ref> 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.<ref>{{cite web | title = Entrez Gene: SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6532}}</ref>

== 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 pump|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.<ref>{{Cite web|url=https://web.williams.edu/imput/synapse/pages/IVB3.html|title=Mechanism of Action of the Serotonin Transporter|website=web.williams.edu|access-date=2016-12-28}}</ref>

== Function ==
The serotonin transporter removes serotonin from the synaptic cleft back into the synaptic [[Chemical synapse#bouton|bouton]]s. Thus, it terminates the effects of serotonin and simultaneously enables its reuse by the [[presynaptic neuron]].<ref name="Squire2008" />

Neurons communicate by using chemical messengers like serotonin between cells. The [[Membrane transport protein|transporter protein]], by recycling serotonin, regulates its concentration in a gap, or [[synapse]], and thus its effects on a receiving neuron's [[receptor (biochemistry)|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]],<ref>{{cite journal | vauthors = Marazziti D, Akiskal HS, Rossi A, Cassano GB | title = Alteration of the platelet serotonin transporter in romantic love | journal = Psychological Medicine | volume = 29 | issue = 3 | pages = 741–745 | date = May 1999 | pmid = 10405096 | doi = 10.1017/S0033291798007946 | s2cid = 12630172 }}</ref> [[hypertension]] and [[social anxiety disorder|generalized social phobia]].<ref>{{cite journal | vauthors = 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-naive patients with generalized social anxiety disorder shown by 123I-beta-(4-iodophenyl)-tropane SPECT | journal = Journal of Nuclear Medicine | volume = 49 | issue = 5 | pages = 757–763 | date = May 2008 | pmid = 18413401 | doi = 10.2967/jnumed.107.045518 | doi-access = free }}</ref>

The serotonin transporter is also present in [[platelet]]s; there, serotonin functions as a [[vasoconstrictive]] substance. It also serves as a signalling molecule to induce platelet aggregation.

<gallery widths=180>
 Image:Serotonin-2D-skeletal.svg|[[Serotonin]]
</gallery>

==Pharmacology==

In 1995 and 1996, scientists in Europe had identified the polymorphism [[5-HTTLPR]], a serotonin-transporter in the gene ''[[SLC6A4]]''.<ref>{{cite journal | vauthors = Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U, Riederer P, Lesch KP | title = Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene | journal = Journal of Neural Transmission. General Section | volume = 102 | issue = 3 | pages = 247–254 | year = 1995 | pmid = 8788073 | doi = 10.1007/BF01281159 | author8-link = K. P. Lesch | s2cid = 8474414 | author7-link = P. Riederer }}</ref><ref>{{cite journal | vauthors = 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 | date = June 1996 | pmid = 8632190 | doi = 10.1046/j.1471-4159.1996.66062621.x | s2cid = 42037860 | author7-link = Klaus-Peter Lesch | author5-link = P. Riederer }}</ref> 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."<ref>{{cite journal | vauthors = 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 | title = A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders | journal = Molecular Psychiatry | volume = 1 | issue = 6 | pages = 453–460 | date = December 1996 | pmid = 9154246 }}</ref>

SERT spans the plasma membrane 12&nbsp;times. It belongs to the NE, DA, SERT monoamine transporter family. Transporters are important sites for agents that treat [[psychiatric disorder]]s. Drugs that reduce the binding of serotonin to transporters ([[serotonin reuptake inhibitor]]s, or SRIs) are used to treat mental disorders. The [[selective serotonin reuptake inhibitor]] (SSRI) [[fluoxetine]] and the [[tricyclic antidepressant]] (TCA) [[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.<ref>{{cite journal | vauthors = Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN | title = LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake | journal = Science | volume = 317 | issue = 5843 | pages = 1390–1393 | date = September 2007 | pmid = 17690258 | pmc = 3711652 | doi = 10.1126/science.1147614 | bibcode = 2007Sci...317.1390Z }}</ref> However, studies on SERT showed that tricyclic antidepressants and selective serotonin reuptake inhibitors bind to the central binding site overlapping the substrate binding site.<ref>{{cite journal | vauthors = Sinning S, Musgaard M, Jensen M, Severinsen K, Celik L, Koldsø H, Meyer T, Bols M, Jensen HH, Schiøtt B, Wiborg O | title = Binding and orientation of tricyclic antidepressants within the central substrate site of the human serotonin transporter | journal = The Journal of Biological Chemistry | volume = 285 | issue = 11 | pages = 8363–8374 | date = March 2010 | pmid = 19948720 | pmc = 2832986 | doi = 10.1074/jbc.M109.045401 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Andersen J, Taboureau O, Hansen KB, Olsen L, Egebjerg J, Strømgaard K, Kristensen AS | title = Location of the antidepressant binding site in the serotonin transporter: importance of Ser-438 in recognition of citalopram and tricyclic antidepressants | journal = The Journal of Biological Chemistry | volume = 284 | issue = 15 | pages = 10276–10284 | date = April 2009 | pmid = 19213730 | pmc = 2665081 | doi = 10.1074/jbc.M806907200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Koldsø H, Severinsen K, Tran TT, Celik L, Jensen HH, Wiborg O, Schiøtt B, Sinning S | title = The two enantiomers of citalopram bind to the human serotonin transporter in reversed orientations | journal = Journal of the American Chemical Society | volume = 132 | issue = 4 | pages = 1311–1322 | date = February 2010 | pmid = 20055463 | doi = 10.1021/ja906923j | bibcode = 2010JAChS.132.1311K }}</ref> 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.<ref>{{cite journal | vauthors = Penmatsa A, Wang KH, Gouaux E | title = X-ray structure of dopamine transporter elucidates antidepressant mechanism | journal = Nature | volume = 503 | issue = 7474 | pages = 85–90 | date = November 2013 | pmid = 24037379 | pmc = 3904663 | doi = 10.1038/nature12533 | bibcode = 2013Natur.503...85P }}</ref>

[[File:Mattson 2005.svg|thumb|177px|'''12a''']] {{stack|[[File:Tamagnan 2005.svg|thumb|190px|'''4b''']]}}

===Ligands===
* [[DASB]]
* compound 4b: ''K''i = 17 pM; 710-fold and 11,100-fold selective over DAT and NET<ref name="pmid15686927">{{cite journal | vauthors = Tamagnan G, Alagille D, Fu X, Kula NS, Baldessarini RJ, Innis RB, Baldwin RM | title = Synthesis and monoamine transporter affinity of new 2beta-carbomethoxy-3beta-[4-(substituted thiophenyl)]phenyltropanes: discovery of a selective SERT antagonist with picomolar potency | journal = Bioorganic & Medicinal Chemistry Letters | volume = 15 | issue = 4 | pages = 1131–1133 | date = February 2005 | pmid = 15686927 | doi = 10.1016/j.bmcl.2004.12.014 }}</ref>
* compound (+)-12a: ''K''i = 180 pM at hSERT; >1000-fold selective over hDAT, hNET, 5-HT<sub>1A</sub>, and 5-HT<sub>6</sub>.<ref name="pmid16162005">{{cite journal | vauthors = 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 | title = Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 19 | pages = 6023–6034 | date = September 2005 | pmid = 16162005 | doi = 10.1021/jm0503291 }}</ref> [[Bioisostere|Isostere]]s<ref name="pmid17766113">{{cite journal | vauthors = 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 | title = Conformationally restricted homotryptamines. Part 4: Heterocyclic and naphthyl analogs of a potent selective serotonin reuptake inhibitor | journal = Bioorganic & Medicinal Chemistry Letters | volume = 17 | issue = 20 | pages = 5647–5651 | date = October 2007 | pmid = 17766113 | doi = 10.1016/j.bmcl.2007.07.083 }}</ref>
* 3-''cis''-(3-Aminocyclopentyl)indole 8a: ''K''i = 220 pM<ref>{{cite journal | vauthors = 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 | title = Conformationally restricted homotryptamines. Part 7: 3-cis-(3-aminocyclopentyl)indoles as potent selective serotonin reuptake inhibitors | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 21 | pages = 7564–7572 | date = November 2010 | pmid = 20949929 | doi = 10.1021/jm100515z }}</ref>
* allosteric modulator: 3′-Methoxy-8-methyl-spiro{8-azabicyclo[3.2.1]octane-3,5′(4′H)-isoxazole} (compound 7a)<ref>{{cite journal | vauthors = Dallanoce C, Canovi M, Matera C, Mennini T, De Amici M, Gobbi M, De Micheli C | title = A novel spirocyclic tropanyl-Δ²-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake | journal = Bioorganic & Medicinal Chemistry | volume = 20 | issue = 21 | pages = 6344–6355 | date = November 2012 | pmid = 23022052 | doi = 10.1016/j.bmc.2012.09.004 }}</ref>
* allosteric modulator: ''p''-Trifluoromethyl-[[methcathinone]]<ref name="pmid31028773">{{cite journal | vauthors = Niello M, Cintulova D, Hellsberg E, Jäntsch K, Holy M, Ayatollahi LH, Cozzi NV, Freissmuth M, Sandtner W, Ecker GF, Mihovilovic MD, Sitte HH | title = para-Trifluoromethyl-methcathinone is an allosteric modulator of the serotonin transporter | journal = Neuropharmacology | volume = 161 | pages = 107615 | date = December 2019 | pmid = 31028773 | doi = 10.1016/j.neuropharm.2019.04.021 | s2cid = 128363044 | doi-access =  }}</ref>

==Genetics==
[[File:Slc6a4, ISH, mouse, dorsal raphe.jpg|thumbnail|[http://mouse.brain-map.org/experiment/show/79591679 Slc6a4] is expressed in median and dorsal raphe in the midbrain of the postnatal day 56 mouse.<ref name="pmid19179540">{{cite journal | vauthors = Dahlin A, Royall J, Hohmann JG, Wang J | title = Expression profiling of the solute carrier gene family in the mouse brain | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 329 | issue = 2 | pages = 558–570 | date = May 2009 | pmid = 19179540 | pmc = 2672879 | doi = 10.1124/jpet.108.149831 }}</ref> [[Allen Brain Atlas]]es]]

[[File:Serotonin transporter 1 in green, tyrosine hydoxylase in red and nuclear DNA in blue in a region of rat brain.jpg|thumb|Serotonin transporter 1 (Slc6a4) in green, [[tyrosine hydroxylase]] in red and nuclear DNA in blue in a region of rat brain stem. Antibody staining and imaging by [[EnCor Biotechnology Inc.]]]]|

[[File:Chromosome 17.svg|125px|thumb|[[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 [[human]]s the gene is found on [[chromosome 17]] on location 17q11.1&ndash;q12.<ref name="NakamuraM2000Human">{{cite journal | vauthors = Nakamura M, Ueno S, Sano A, Tanabe H | title = The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants | journal = Molecular Psychiatry | volume = 5 | issue = 1 | pages = 32–38 | date = January 2000 | pmid = 10673766 | doi = 10.1038/sj.mp.4000698 | s2cid = 12459610 | doi-access =  }}</ref>

Mutations associated with the gene may result in changes in serotonin transporter function, and experiments with [[mouse|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 (zoology)|gut]] dysfunction.<ref name="MurphyD2008Targeting">{{cite journal | vauthors = Murphy DL, Lesch KP | title = Targeting the murine serotonin transporter: insights into human neurobiology | journal = Nature Reviews. Neuroscience | volume = 9 | issue = 2 | pages = 85–96 | date = February 2008 | pmid = 18209729 | doi = 10.1038/nrn2284 | s2cid = 7563088 }}</ref>
Some of the human genetic variations associated with the gene are:<ref name="MurphyD2008Targeting"/>
* Length variation in the serotonin-transporter-gene-linked polymorphic region ([[5-HTTLPR]])
* [[rs25531]] &mdash; a [[single nucleotide polymorphism]] (SNP) in the 5-HTTLPR
* [[rs25532]] &mdash; another SNP in the 5-HTTLPR
* STin2 &mdash; 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 ===
{{main|5-HTTLPR}}

According to a 1996 article in ''The Journal of Neurochemistry'', the [[promoter (biology)|promoter]] region of the SLC6A4 gene contains a [[Polymorphism (biology)|polymorphism]] with "short" and "long" repeats in a region: 5-HTT-linked polymorphic region ([[5-HTTLPR]] or ''SERTPR'').<ref>{{cite journal | vauthors = 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 | date = June 1996 | pmid = 8632190 | doi = 10.1046/j.1471-4159.1996.66062621.x | s2cid = 42037860 }}</ref>
The short variation has 14 repeats of a sequence while the long variation has 16 repeats.<ref name="NakamuraM2000Human"/> A second 1996 article stated that the short variation leads to less [[transcription (genetics)|transcription]] for SLC6A4, and it has been found that it can partly account for anxiety-related [[personality trait]]s.<ref>{{cite journal | vauthors = Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL | title = Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region | journal = Science | volume = 274 | issue = 5292 | pages = 1527–1531 | date = November 1996 | pmid = 8929413 | doi = 10.1126/science.274.5292.1527 | s2cid = 35503987 | bibcode = 1996Sci...274.1527L }}</ref> This polymorphism has been extensively investigated in over 300 scientific studies (as of 2006).<ref>{{cite journal | vauthors = Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL | title = Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531 | journal = Molecular Psychiatry | volume = 11 | issue = 3 | pages = 224–226 | date = March 2006 | pmid = 16402131 | doi = 10.1038/sj.mp.4001789 | s2cid = 26655014 | doi-access =  }}</ref> The 5-HTTLPR polymorphism may be subdivided further:
One study published in 2000 found 14 [[allele|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 people|Japanese]] and [[Caucasian race|Caucasian]] people.<ref name="NakamuraM2000Human"/>

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.<ref name="Pezawas2005">{{cite journal | vauthors = 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 | pages = 828–834 | date = June 2005 | pmid = 15880108 | doi = 10.1038/nn1463 | s2cid = 1864631 }}</ref>

In contrast, a 2008 meta-analysis found no significant overall association between the 5-HTTLPR polymorphism and autism.<ref name=Huang-Santangelo>{{cite journal | vauthors = Huang CH, Santangelo SL | title = Autism and serotonin transporter gene polymorphisms: a systematic review and meta-analysis | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 147B | issue = 6 | pages = 903–913 | date = September 2008 | pmid = 18286633 | doi = 10.1002/ajmg.b.30720 | s2cid = 9491697 }}</ref> A hypothesized [[gene–environment interaction]] between the short/short allele of the 5-HTTLPR and life stress as predictor for [[major depressive disorder|major depression]] has suffered a similar fate: after an influential<ref>{{cite journal | vauthors = Nierenberg AA | title = The long tale of the short arm of the promoter region for the gene that encodes the serotonin uptake protein | journal = CNS Spectrums | volume = 14 | issue = 9 | pages = 462–463 | date = September 2009 | pmid = 19890228 | doi = 10.1017/s1092852900023506 | s2cid = 24236284 }}</ref> initial report in 2003<ref>{{cite journal | vauthors = Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R | title = Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene | journal = Science | volume = 301 | issue = 5631 | pages = 386–389 | date = July 2003 | pmid = 12869766 | doi = 10.1126/science.1083968 | s2cid = 146500484 | bibcode = 2003Sci...301..386C }}</ref> there were mixed results in replication in 2008,<ref>{{cite journal | vauthors = Uher R, McGuffin P | title = The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis | journal = Molecular Psychiatry | volume = 13 | issue = 2 | pages = 131–146 | date = February 2008 | pmid = 17700575 | doi = 10.1038/sj.mp.4002067 | s2cid = 24432263 | doi-access =  }}</ref> and a 2009 meta-analysis was negative.<ref>{{cite journal | vauthors = Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR | title = Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis | journal = JAMA | volume = 301 | issue = 23 | pages = 2462–2471 | date = June 2009 | pmid = 19531786 | pmc = 2938776 | doi = 10.1001/jama.2009.878 }}</ref> 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).<ref>{{cite journal | vauthors = 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 = 717–723 | date = March 2008 | pmid = 18055562 | doi = 10.1093/hmg/ddm343 | doi-access = free }}</ref>

=== 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.<ref>{{cite journal | vauthors = 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 | issue = 11 | pages = 933–936 | date = November 2003 | pmid = 14593431 | doi = 10.1038/sj.mp.4001365 | s2cid = 2171955 | doi-access =  }}
News article:
* {{Cite news
 |agency       = Reuters
 |title        = Gene Found for Obsessive-Compulsive Disorder
 |publisher    = Mental Health E-News
 |date         = 27 October 2003
 |url          = http://www.nyaprs.org/Pages/View_ENews.cfm?ENewsID=2842
 |access-date   = 25 January 2008
 |archive-url  = https://web.archive.org/web/20061006182857/http://www.nyaprs.org/Pages/View_ENews.cfm?ENewsID=2842
 |archive-date = 6 October 2006
 |url-status     = dead
 |df           = dmy-all
}}</ref><ref>
{{cite journal | vauthors = 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 | volume = 10 | issue = 12 | pages = 1059–1061 | date = December 2005 | pmid = 16088327 | pmc = 2547479 | doi = 10.1038/sj.mp.4001728 }}</ref><ref>{{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
 | access-date = 12 June 2008
}}</ref>

=== VNTR in STin2 ===
Another noncoding polymorphism is a [[VNTR]] in the second [[intron]] ([[STin2]]). In a 2005 study, it was found with three [[allele]]s: 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]].<ref>{{cite journal | vauthors = Fan JB, Sklar P | title = Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia | journal = Molecular Psychiatry | volume = 10 | issue = 10 | pages = 928–38, 891 | date = October 2005 | pmid = 15940296 | doi = 10.1038/sj.mp.4001690 | s2cid = 29240701 | doi-access =  }}</ref>
A 2008 meta-analysis found no significant overall association between the STin2 VNTR polymorphism and [[autism]].<ref name=Huang-Santangelo/>
Furthermore, a 2003 meta-analysis of [[affective disorder]]s, [[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.<ref>{{cite journal | vauthors = 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 | volume = 8 | issue = 6 | pages = 574–591 | date = June 2003 | pmid = 12851635 | doi = 10.1038/sj.mp.4001328 | doi-access = free }}</ref>

The polymorphism has also been related to [[personality trait]]s with a 2008 Russian study finding individuals with the STin2.10 allele having lower [[neuroticism]] scores as measured with the [[Eysenck Personality Inventory]].<ref>{{cite journal | vauthors = 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 = 167–176 | date = August 2008 | pmid = 18628678 | doi = 10.1097/YPG.0b013e328304deb8 | s2cid = 7423923 }}</ref>

== Neuroimaging ==
The distribution of the serotonin transporter in the [[brain]] may be imaged with [[positron emission tomography]] using [[radioligand]]s called [[3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile|DASB]] and DAPP; the first such studies on the human brain were reported in 2000.<ref name="pmid11105830">{{cite journal | vauthors = 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 | volume = 27 | issue = 11 | pages = 1719–1722 | date = November 2000 | pmid = 11105830 | doi = 10.1007/s002590000365 | s2cid = 18932686 }}</ref> 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 [[isotopes of iodine|iodine-123]] [[isotope]] that is used for brain scanning with ''[[single-photon emission computed tomography]]'' (SPECT) according to a 1993 article in the ''Journal of Neural Transmission''.<ref name="pmid8110440">{{cite journal | vauthors = Brücke T, Kornhuber J, Angelberger P, Asenbaum S, Frassine H, Podreka I | title = SPECT imaging of dopamine and serotonin transporters with [123I]beta-CIT. Binding kinetics in the human brain | journal = Journal of Neural Transmission. General Section | volume = 94 | issue = 2 | pages = 137–146 | year = 1993 | pmid = 8110440 | doi = 10.1007/BF01245007 | s2cid = 22034290 }}</ref> The radioligands were used in 2006 to examine whether variables such as age, gender or [[genotype]] are associated with differential serotonin transporter binding.<ref>{{Cite journal | vauthors = Brust P, Hesse S, Muller U, Szabo Z | title = Neuroimaging of the Serotonin Transporter &mdash; Possibilities and Pitfalls | journal = Current Psychiatry Reviews | date = February 2006 | volume = 2 | issue = 1 | pages = 111&ndash;149 | url = http://www-bmu.psychiatry.cam.ac.uk/publications/brust06neu.pdf | doi = 10.2174/157340006775101508 | url-status = dead | archive-url = https://web.archive.org/web/20110723033800/http://www-bmu.psychiatry.cam.ac.uk/publications/brust06neu.pdf | archive-date = 23 July 2011 | df = dmy-all }}</ref> Healthy subjects that have a high score of [[neuroticism]]&mdash;a [[Trait theory|personality trait]] in the [[Revised NEO Personality Inventory]]&mdash;were found to have more serotonin transporter binding in the [[thalamus]] in 2007.<ref name="pmid17336939">{{cite journal | vauthors = 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 | pages = 588–592 | date = September 2007 | pmid = 17336939 | doi = 10.1016/j.biopsych.2006.11.007 | s2cid = 41664835 }}</ref>

== 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.<ref name="Pezawas2005" />

== References ==
{{Reflist|33em}}

{{Commons category|Serotonin transporters}}
{{Membrane transport proteins}}
{{Neurotransmitter transporters}}
{{Monoamine reuptake inhibitors}}
{{Monoamine releasing agents}}

[[Category:Membrane proteins]]
[[Category:Neurotransmitter transporters]]
[[Category:Solute carrier family]]
[[Category:Molecular neuroscience]]
[[Category:Biology of bipolar disorder]]
[[Category:Amphetamine]]
[[Category:Genes on human chromosome 17]]
[[Category:Serotonin]]