# SLC6A4

## Overview
The SLC6A4 gene encodes the solute carrier family 6 member 4 protein, commonly known as the serotonin transporter (SERT), which is a critical component in the regulation of serotonin levels in the central nervous system. SERT is a transmembrane protein that belongs to the neurotransmitter sodium symporter (NSS) family, characterized by its 12 transmembrane domains that facilitate the reuptake of serotonin from the synaptic cleft back into presynaptic neurons (Gurbanov2019SLC6A4; Pramod2013SLC6). This reuptake process is essential for terminating serotonin signaling and maintaining neurotransmitter homeostasis, thereby influencing mood, emotion, and behavior (Murphy2008How). The gene's expression and function are modulated by various genetic variants, which have been associated with psychiatric and neurodevelopmental disorders, including anxiety, depression, and autism (Sutcliffe2005Allelic; Murphy2008How). SERT's interactions with other proteins and its regulation by post-translational modifications further underscore its complex role in serotonergic signaling and its potential as a therapeutic target (Chanrion2007Physical; Zhu2011Colocalization).

## Structure
The SLC6A4 gene encodes the serotonin transporter (SERT), a protein integral to serotonin reuptake in the synaptic cleft. The primary structure of SERT consists of 630 amino acids (Gurbanov2019SLC6A4; Murphy2008How). Its secondary structure includes 12 transmembrane domains, which are typical of the neurotransmitter sodium symporter (NSS) family (Gurbanov2019SLC6A4; Murphy2008How). These transmembrane domains form a 5 + 5 helical architecture, with TMs 1-5 and TMs 6-10 creating two antiparallel pentahelical bundles, while TMs 11 and 12 are peripheral (Pramod2013SLC6).

The tertiary structure involves the arrangement of these helices within the membrane, facilitating the transport of serotonin by coupling with sodium and chloride ions (Gurbanov2019SLC6A4). SERT may form homodimers, indicating a quaternary structure (Pramod2013SLC6). The protein undergoes post-translational modifications, including N-linked glycosylation at two sites on a large extracellular loop between transmembrane domains 3 and 4, which is crucial for its function (Gurbanov2019SLC6A4). Splice variants of SLC6A4 can result in different isoforms with altered functions, impacting serotonin transport and associated physiological processes (Hasan2021The).

## Function
The SLC6A4 gene encodes the serotonin transporter (SERT), a protein crucial for the reuptake of serotonin from the synaptic cleft back into presynaptic neurons. This process is essential for terminating serotonin action and regulating its levels in the brain, which influences mood, emotion, and behavior (Murphy2008How; CHAMBA2008Characterisation). SERT is a high-affinity plasma membrane transporter and part of the SLC6 gene family, which includes transporters for other neurotransmitters like dopamine and norepinephrine (CHAMBA2008Characterisation).

In healthy human cells, SERT maintains serotonin homeostasis, which is crucial for mood regulation and other physiological processes (Murphy2008How). The protein is primarily active in the central nervous system, particularly in serotonergic neurons, but is also present in peripheral tissues, including platelets, lymphocytes, and epithelial cells of the gastrointestinal mucosa (CHAMBA2008Characterisation; Murphy2008How). In the gut, SERT regulates serotonin activity by terminating its action in the mucosa and enteric nervous system, influencing gut motility and function (Murphy2008How). Variations in the SLC6A4 gene can lead to differences in serotonin uptake and transporter function, impacting various physiological and psychological traits (Murphy2008How).

## Clinical Significance
The SLC6A4 gene, encoding the serotonin transporter, is implicated in various psychiatric and neurodevelopmental disorders due to its role in serotonin regulation. Variants of SLC6A4, such as 5HTTLPR and SNPs rs25531 and rs25532, influence the gene's transcriptional activity and are associated with conditions like anxiety, depression-related traits, and obsessive-compulsive disorder (OCD) (Murphy2008How). The 5HTTLPR variant, in particular, has been linked to anxiety and affective disorders through gene-environment interactions (Murphy2008How).

In autism, allelic heterogeneity at the SLC6A4 locus contributes to susceptibility, with specific variants like Gly56Ala associated with increased rigid-compulsive behaviors and sensory aversion (Sutcliffe2005Allelic; VeenstraVanderWeele2009Modeling). The Gly56Ala variant shows elevated serotonin transporter activity, which may influence autism traits (Sutcliffe2005Allelic).

SLC6A4 is also linked to OCD, with the Ileu425Val variant showing a significant association with the disorder. This variant results in a gain-of-function, leading to increased serotonin uptake (Murphy2008How). The gene's involvement in panic disorder has been suggested, although the promoter region 5-HTTLPR was not found to be associated (Strug2008Panic).

## Interactions
The SLC6A4 gene encodes the serotonin transporter (SERT), which is involved in various protein interactions that regulate its function and localization. SERT interacts with neuronal nitric oxide synthase (nNOS), a PDZ domain-containing protein, through a PDZ binding motif. This interaction affects SERT's cell surface localization and serotonin uptake, with nNOS reducing SERT activity in vivo (Chanrion2007Physical). Syntaxin 1A is another protein that interacts with SERT, modulating its activity (Chanrion2007Physical).

SERT also interacts with the A3 adenosine receptor (A3 AR), which enhances SERT activity through pathways involving protein kinase G1 (PKGI) and p38 MAPK, increasing SERT surface expression and catalytic activation (Zhu2011Colocalization). The secretory carrier membrane protein 2 (SCAMP2) interacts with SERT, reducing its surface density and uptake activity (Zhong2012Consideration).

The Ala56 variant of SERT shows altered interactions with several proteins, including decreased association with flotillin-1 (FLOT1) and serine/threonine kinases, and increased interaction with septins and the fragile X mental retardation 1 protein (FMR1) (Quinlan2020Ex). These interactions suggest complex regulatory mechanisms involving SERT and its protein partners.


## References


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[3. (Zhong2012Consideration) Huailing Zhong, Connie Sánchez, and Marc G. Caron. Consideration of allosterism and interacting proteins in the physiological functions of the serotonin transporter. Biochemical Pharmacology, 83(4):435–442, February 2012. URL: http://dx.doi.org/10.1016/j.bcp.2011.09.020, doi:10.1016/j.bcp.2011.09.020. This article has 36 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.bcp.2011.09.020)

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[5. (Hasan2021The) Md. Amit Hasan, Fuad Taufiqul Hakim, Md. Tanjil Islam Shovon, Md. Mirajul Islam, Md. Samiul Islam, and Md. Asadul Islam. The investigation of nonsynonymous snps of human slc6a4 gene associated with depression: an in silico approach. Heliyon, 7(8):e07815, August 2021. URL: http://dx.doi.org/10.1016/j.heliyon.2021.e07815, doi:10.1016/j.heliyon.2021.e07815. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.heliyon.2021.e07815)

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[9. (Murphy2008How) Dennis L. Murphy, Meredith A. Fox, Kiara R. Timpano, Pablo R. Moya, Renee Ren-Patterson, Anne M. Andrews, Andrew Holmes, Klaus-Peter Lesch, and Jens R. Wendland. How the serotonin story is being rewritten by new gene-based discoveries principally related to slc6a4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. Neuropharmacology, 55(6):932–960, November 2008. URL: http://dx.doi.org/10.1016/j.neuropharm.2008.08.034, doi:10.1016/j.neuropharm.2008.08.034. This article has 178 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.neuropharm.2008.08.034)

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