serotonin transporter by m.atifarif

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									Serotonin transporter
From Wikipedia, the free encyclopedia
 Jump to: navigation, search Solute carrier family 6 (neurotransmitter
transporter, serotonin), member 4
Identifiers
Symbols     SLC6A4; 5-HTT; 5-HTTLPR; 5HTT; HTT; OCD1; SERT; SERT1; hSERT
External IDs      OMIM: 182138 MGI: 96285 HomoloGene: 817 ChEMBL: 228
GeneCards: SLC6A4 Gene
[show]
Gene Ontology

RNA expression pattern

More reference expression data
Orthologs
Species    Human Mouse
Entrez     6532 15567
Ensembl    ENSG00000108576 ENSMUSG00000020838
UniProt    P31645       Q60857
RefSeq (mRNA)     NM_001045.4 NM_010484.2
RefSeq (protein) NP_001036.1 NP_034614.2
Location (UCSC) Chr 17:
 28.52 – 28.56 Mb Chr 11:
 76.81 – 76.85 Mb
PubMed search     [1]   [2]
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The serotonin transporter (SERT) is a monoamine transporter protein.

This protein 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
the target of many antidepressant medications, including those of the
SSRI class.[1] 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.[2]Contents [hide]
1 Function
2 Pharmacology
2.1 Ligands
3 Genetics
3.1 Length variation in 5-HTTLPR
3.2 rs25532
3.3 I425V
3.4 VNTR in STin2
4 Neuroimaging
5 Neuroimaging and genetics
6 References
7 Further reading
[edit]
Function

The serotonin transporter removes serotonin from the synaptic cleft back
into the synaptic boutons. Thus, it terminates the effects of serotonin
and simultaneously enables its reuse by the presynaptic neuron.[1]

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 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,[3] hypertension and generalized social phobia.[4]

The serotonin transporter is also present in platelets; there, serotonin
functions as a vasoconstrictive substance.

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. Both drugs that reduce the binding of
serotonin to transporters (selective serotonin reuptake inhibitors, or
SSRIs) and, less often, that increase it (selective serotonin reuptake
enhancers, or SSREs) 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, and tianeptine is an example of a
selective serotonin reuptake enhancer.

12a

4b
[edit]
Ligands
compound (+)-12a: Ki = 180 pM at hSERT; >1000-fold selective over hDAT,
hNET, 5-HT1A, and 5-HT6.[5] Isosteres[6]
compound 4b: Ki = 17 pM; 710-fold and 11,100-fold selective over DAT and
NET[7]
3-cis-(3-Aminocyclopentyl)indole 8a: 220pM[8]
[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.[9]
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.[10] Some of the human genetic variations associated with the
gene are:[10]
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
Main article: 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).[11] The short variation has 14 repeats of a
sequence while the long variation has 16 repeats.[9] The short variation
leads to less transcription for SLC6A4, and it has been found that it can
partly account for anxiety-related personality traits.[12] This
polymorphism has been extensively investigated in over 300 scientific
studies (as of 2006).[13] 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.[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.[14]

In contrast, a 2008 meta-analysis found no significant overall
association between the 5-HTTLPR polymorphism and autism.[15] A
hypothesized gene-environment interaction between the short/short allele
of the 5-HTTLPR and life stress as predictor for major depression has
suffered a similar fate: after an influential[16] initial report[17]
there were mixed results in replication,[18] and a 2009 meta-analysis was
negative.[19] See 5-HTTLPR for more information.
[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).[20]
[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.[21][22][23]
[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 statistically significant association
with schizophrenia.[24] A 2008 meta-analysis found no significant overall
association between the STin2 VNTR polymorphism and autism.[15]
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.[25]

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.[26]
[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.[27]
DASB and DAPP are not the only radioligands for the serotonin
transporter. There are numerous others, with the most popular probably
being the ß-CIT radioligand with an iodine-123 isotope that is used for
brain scanning with single photon emission computed tomography
(SPECT).[28] The radioligands have been used to examine whether variables
such as age, gender or genotype are associated with differential
serotonin transporter binding.[29] 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.[30]
[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.[14]

								
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