Serotonin transporter

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

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.^[1]

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Function

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^[2] and hypertension.

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.^[3]

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.^{[citation needed]}

Noncoding polymorphisms

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).^[4] The short variation has 14 repeats of a sequence while the long variation has 16 repeats.^[3] The short variation leads to less transcription for SLC6A4, and it has been found that it can partly account for anxiety-related personality traits.^[5] This polymorphism has been extensively investigated in over 300 scientific studies (as of 2006).^[6] 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.^[3]

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.^[7]

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.^[8]

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.^[9] 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).^[10] The radioligands have been used to examine whether variables such as age, gender or genotype is associated with differential serotonin transporter binding.^[11] 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.^[12]

Methodological issues

When the neuroimages from a DASB experiment are analyzed the kinetic models suggested by Ichise and coworkers^[13] are often employed to estimate the binding potential. A test-retest reproducibility experiment has been performed to evaluate this approach for DASB.^[14]

Neuroimaging 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.^[15]

References

Further reading