Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4
|RNA expression pattern|
This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. The encoded protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is a target of psychomotor stimulants, such as amphetamines and cocaine, 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, and depression-susceptibility in people experiencing emotional trauma.
It reuptakes serotonin in synaptic cleft and terminate 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 and hypertension.
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.
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.
There are a number of other names for this gene, e.g., in humans it may be referred to as hSERT. Other aliases are 5-HTT, 5HTT, HTT, OCD1 and SERT according to GeneCards.
Researchers have found an uncommon mutation in SLC6A4, in some unrelated families with OCD, that 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.
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). 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.
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.
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.
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 a 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 is 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.
When the neuroimages from a DASB experiment are analyzed the kinetic models suggested by Ichise and coworkers are often employed to estimate the binding potential. A test-retest reproducibility experiment has been performed to evaluate this approach for DASB.
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.
- ↑ Entrez Gene: SLC6A4 solute carrier family 6 (neurotransmitter transporter, serotonin), member 4.
- ↑ Donatella Marazziti, H.S. Akiskal, A. Rossi, G.B. Cassano (May 1999). "Alteration of the platelet serotonin transporter in romantic love.". Psychological Medicine 29 (3): 741-745. PMID 10405096.
- ↑ 3.0 3.1 3.2 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: 32–38.
- ↑ Armin Heils, Andreas Teufel, Susanne Petri, Gerald Stöber, Peter Riederer, Dietmar Bengel, & K. Peter Lesch (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.
- ↑ Klaus-Peter Lesch, Dietmar Bengel, Armin Heils, Sue Z. Sabol, Benjamin D. Greenberg, Susanne Petri, Jonathan Benjamin, Clemens R. Müller, Dean H. Hamer, Dennis L. Murphy (November 1996). "Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region". Science 274 (5292). doi:10.1126/science.274.5292.1527.
- ↑ J.R. Wendland, B.J. Martin, M.R. Kruse, K.-P. Lesch, D.L. Murphy (2006). "Simultaneous genotyping of four functional loci of human SLCA4, with a reappraisal of 5-HTTLPR and rs255531". Molecular Psychiatry: 1-3. doi:10.1038/sj.mp.4001789.
- ↑ Dean G. Kilpatrick, Koenen KC, Ruggiero KJ, Acierno R, Galea S, Resnick HS, Roitzsch J, Boyle J, Joel Gelernter (November 2007). "The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults". The American Journal of Psychiatry 164 (11): 1693–1699. PMID 17974934.
- ↑ J. B. Fan & P. Sklar (October 2005). "Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia". Molecular Psychiatry 10 (10): 928–938. PMID 15940296.
- ↑ S. Houle, N. Ginovart, D. Hussey, J.H. Meyer, A.A. Wilson (October 2000). "Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB". European Journal of Nuclear Medicine and Molecular Imaging 27 (11). doi:10.1007/s002590000365.
- ↑ T. Brücke, J. Kornhuber, P. Angelberger, S. Asenbaum, H. Frassine, I. Podreka (June 1993). "SPECT imaging of dopamine and serotonin transporters with [123Iβ-CIT. Binding kinetics in the human brain]". Journal of Neural Transmission 94 (2): 137–146. doi:10.1007/BF01245007.
- ↑ Peter Brust, Swen Hess and Ulrich Müller and Zsolt Szabo (February 2006). "Neuroimaging of the Serotonin Transporter — Possibilities and Pitfalls". Current Psychiatry Reviews 2 (1): 111–149.
- ↑ Akihiro Takano, Ryosuke Arakawaa, Mika Hayashia, Hidehiko Takahashia, Hiroshi Itoa & Tetsuya Suhara (September 2007). "Relationship between neuroticism personality trait and serotonin transporter binding". Biological Psychiatry 62 (6): 588–592. doi:10.1016/j.biopsych.2006.11.007. PMID 17336939.
- ↑ Masanori Ichise, Jeih-San Liow, Jian-Qiang Lu, Akihiro Takano, Kendra Model, Hiroshi Toyama, Tetsuya Suhara, Kazutoshi Suzuki, Robert B Innis and Richard E Carson (2003). "Linearized Reference Tissue Parametric Imaging Methods: Application to [11C]DASB Positron Emission Tomography Studies of the Serotonin Transporter in Human Brain". Journal of Cerebral Blood Flow & Metabolism 23: 1096–1112. doi:10.1097/01.WCB.0000085441.37552.CA.
- ↑ Jae Seung Kim, Masanori Ichise, Janet Sangare, and Robert B. Innis (2006). "PET Imaging of Serotonin Transporters with [11C]DASB: Test–Retest Reproducibility Using a Multilinear Reference Tissue Parametric Imaging Method". Journal of Nuclear Medicine 47 (2): 208-214.
- ↑ Lukas Pezawas, Andreas Meyer-Lindenberg, Emily M. Drabant, Beth A. Verchinski, Karen E. Munoz, Bhaskar S. Kolachana, Michael F. Egan, Venkata S. Mattay, Ahmaad R. Hariri & Daniel R. Weinberger (June 2005). "5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression". Nature Neuroscience 8 (6). doi:10.1038/nn1463.
- Norio Ozak et al. (2003). "Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype". Molecular Psychiatry 8 (11): 933-936.
- NIH press release: Serotonin Transporter Gene Shown to Influence College Drinking Habits
- J.P. Roiser, L.J. Cook, J.D. Cooper, D.C. Rubinsztein, B.J. Sahakian (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.
- 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 Behav. 2 (6): 332-5. 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.
Membrane transport protein: neurotransmitter transporters
|Vesicular||Vesicular monoamine (VMAT1, VMAT2) - Vesicular acetylcholine|
|Other||Glutamate - Monoamine (DAT, NET, SERT)|
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