Serotonin transporter

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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 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, post-traumatic stress disorder and depression-susceptibility in people experiencing emotional trauma.^[1]

[edit] 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^[2], hypertension and generalized social phobia^[3].

Serotonin

[edit] 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.

[edit] Genetics

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 humans the gene is found on chromosome 17 on location 17q11.1–q12.^[4]

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.^[5] Some of the genetic variations associated with the gene are:^[5]

• 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

[edit] 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).^[6] The short variation has 14 repeats of a sequence while the long variation has 16 repeats.^[4] The short variation leads to less transcription for SLC6A4, and it has been found that it can partly account for anxiety-related personality traits.^[7] This polymorphism has been extensively investigated in over 300 scientific studies (as of 2006).^[8] 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.^[4]

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.^[9]

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.^[10] 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.^[11] In contrast, a 2008 meta-analysis found no significant overall association between the 5-HTTLPR polymorphism and autism.^[12]

[edit] 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).^[13]

[edit] 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.^[14][15]

[edit] 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.^[16] A 2008 meta-analysis found no significant overall association between the STin2 VNTR polymorphism and autism.^[12] 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.^[17]

[edit] 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.^[18] 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).^[19] The radioligands have been used to examine whether variables such as age, gender or genotype are associated with differential serotonin transporter binding.^[20] 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.^[21]

[edit] Methodological issues

When the neuroimages from a DASB experiment are analyzed the kinetic models suggested by Ichise and coworkers^[22] are often employed to estimate the binding potential. A test-retest reproducibility experiment has been performed to evaluate this approach for DASB.^[23]

[edit] 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.^[24]

[edit] References

[edit] Further reading