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2.A.22.1.1
Serotonin (5-hydroxytryptamine; 5 HT):Na+:Cl- symporter, SERT.A  Also transports amphetamines; blocked by cocaine and tricyclic antidepressants such as Prozac; interacts directly with the secretory carrier-associated membrane protein-2 (SCAMP2; O15127) to regulate the subcellular distribution (Muller et al., 2006). Uses an alternating sites mechanism with all 3 substrates bound (Zhang and Rudnick, 2006).  Molecular determinants for antidepressants in the human serotonin and norepinephrine  transporters have been identified (Andersen et al., 2011). A conserved asparagine residue in transmembrane segment 1 (TMS1) of the serotonin transporter dictates chloride-coupled neurotransmitter transport (Henry et al., 2011). The formation and breakage of ionic interactions with amino acids in transmembrane helices 6 and 8 and intracellular loop 1 may be of importance for substrate translocation (Gabrielsen et al., 2012). Methylation of the SLC6A4 gene promoter controls depression in men by an epigenetic mechanism (Devlin et al., 2010).  The 5HT Km is 0.4 micromolar (Banovic et al. 2010).  Regulated allosterically by ATM7 which stabilizes the outward-facing conformation of SERT (Kortagere et al. 2013).  Functional and regulatory mechanisms involving the N- and C-terminal hydrophilic domains have been considered (Fenollar-Ferrer et al. 2014).  The range of substrates bound and transported has been predicted (Kaufmann et al. 2009).  TMS3 may function in substrate and antagonist recognition (Walline et al. 2008).  The 3-d x-ray structure with antidepressants bound have been solved, leading to mechanistic predictions; antidepressants lock SERT in an outward- open conformation by lodging in the central binding site, located between transmembrane helices 1, 3, 6, 8 and 10, directly blocking serotonin binding (Coleman et al. 2016).  Na+ and cocaine stabilize outward-open conformations of SERT and decrease phosphorylation while agents that stabilize inward-open conformations (e.g., 5-HT, ibogaine) increase phosphorylation. The opposing effects of the inhibitors, cocaine and ibogaine, were each reversed by an excess of the other inhibitor. Inhibition of phosphorylation by Na+ and stimulation by ibogaine occurred at concentrations that induced outward opening and inward opening, respectively (Zhang et al. 2016).  SERT is regulated by multiple molecular mechanisms including its physical interaction with intracellular proteins including the ASCT2 (alanine-serine-cysteine-threonine 2; TC# 2.A.23.3.2), co-expressed with SERT in serotonergic neurons and involved in the transport of small neutral amino acids across the plasma membrane (Seyer et al. 2016).  Transports substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) (Sealover et al. 2016).  A naturally occurring mutation, I425V, associated with obsessive-compulsive disorder and other neuropsychiatric disorders, activates hSERT and eliminates stimulation via the cyclicGMP-dependent pathway (Zhang et al. 2007).  The substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy), is a widely used drug of abuse that induces non-exocytotic release of serotonin, dopamine, and norepinephrine through their cognate transporters as well as blocking the reuptake of neurotransmitter by the same transporters. In this transporter, Glu394 plays a role in MDMA recognition (Sealover et al. 2016). Intestinal dysbiosis may upregulate SERT expression and contribute to the development of chronic constipation (Cao et al. 2017).

Accession Number:P31645
Protein Name:NTSE aka SLC6A4 aka HTT aka SERT
Length:630
Molecular Weight:70325.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:11
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate serotonin, Na+, Cl-

Cross database links:

Genevestigator: P31645 P31645
eggNOG: prNOG09075 COG0733
HEGENOM: HBG702834 HOG000116406
RefSeq: NP_001036.1   
Entrez Gene ID: 6532   
Pfam: PF03491    PF00209   
Drugbank: Drugbank Link   
OMIM: 103780  phenotype
164230  phenotype
182138  gene
KEGG: hsa:6532    hsa:6532   

Gene Ontology

GO:0005829 C:cytosol
GO:0005887 C:integral to plasma membrane
GO:0008022 F:protein C-terminus binding
GO:0015222 F:serotonin transmembrane transporter activity
GO:0005335 F:serotonin:sodium symporter activity
GO:0009636 P:response to toxin
GO:0051610 P:serotonin uptake
GO:0021794 P:thalamus development
GO:0012505 C:endomembrane system
GO:0010008 C:endosome membrane
GO:0045121 C:membrane raft
GO:0019717 C:synaptosome
GO:0019811 F:cocaine binding
GO:0048854 P:brain morphogenesis
GO:0071321 P:cellular response to cGMP
GO:0071300 P:cellular response to retinoic acid
GO:0007623 P:circadian rhythm
GO:0007613 P:memory
GO:0021941 P:negative regulation of cerebellar granule cell precursor proliferation
GO:0045665 P:negative regulation of neuron differentiation
GO:0046621 P:negative regulation of organ growth
GO:0032227 P:negative regulation of synaptic transmission, dopaminergic
GO:0045787 P:positive regulation of cell cycle
GO:0010628 P:positive regulation of gene expression
GO:0051260 P:protein homooligomerization
GO:0051259 P:protein oligomerization
GO:0042493 P:response to drug
GO:0032355 P:response to estradiol stimulus
GO:0001666 P:response to hypoxia
GO:0035176 P:social behavior
GO:0042713 P:sperm ejaculation
GO:0042310 P:vasoconstriction

References (26)

[1] “Isolation of a cDNA encoding the human brain serotonin transporter.”  Lesch K.P.et.al.   8452685
[2] “Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization.”  Ramamoorthy S.et.al.   7681602
[3] “Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter.”  Lesch K.P.et.al.   7684072
[4] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[5] “Serotonin-, protein kinase C-, and Hic-5-associated redistribution of the platelet serotonin transporter.”  Carneiro A.M.D.et.al.   16803896
[6] “Characterization of single-nucleotide polymorphisms in coding regions of human genes.”  Cargill M.et.al.   10391209
[7] “Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype.”  Ozaki N.et.al.   14593431
[8] “A human serotonin transporter mutation causes constitutive activation of transport activity.”  Kilic F.et.al.   12869649
[9] “Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.”  Caspi A.et.al.   12869766
[10] “Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence.”  Feinn R.et.al.   15635638
[11] “Isolation of a cDNA encoding the human brain serotonin transporter.”  Lesch K.P.et.al.   8452685
[12] “Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization.”  Ramamoorthy S.et.al.   7681602
[13] “Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter.”  Lesch K.P.et.al.   7684072
[14] “Molecular characterization and intracellular regulation of the human serotonin transporter in Caco-2 cells.”  Iceta R.et.al.   16601320
[15] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[16] “Serotonin-, protein kinase C-, and Hic-5-associated redistribution of the platelet serotonin transporter.”  Carneiro A.M.D.et.al.   16803896
[17] “Subcellular redistribution of the serotonin transporter by secretory carrier membrane protein 2.”  Mueller H.K.et.al.   16870614
[18] “Plasma serotonin levels and the platelet serotonin transporter.”  Brenner B.et.al.   17506858
[19] “Serotonin transamidates Rab4 and facilitates its binding to the C terminus of serotonin transporter.”  Ahmed B.A.et.al.   18227069
[20] “The cellular distribution of serotonin transporter is impeded on serotonin-altered vimentin network.”  Ahmed B.A.et.al.   19270731
[21] “Tyrosine phosphorylation of the human serotonin transporter: a role in the transporter stability and function.”  Annamalai B.et.al.   21992875
[22] “Characterization of single-nucleotide polymorphisms in coding regions of human genes.”  Cargill M.et.al.   10391209
[23] “Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype.”  Ozaki N.et.al.   14593431
[24] “A human serotonin transporter mutation causes constitutive activation of transport activity.”  Kilic F.et.al.   12869649
[25] “Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene.”  Caspi A.et.al.   12869766
[26] “Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence.”  Feinn R.et.al.   15635638
Structure:
5i6x   5i6z     

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FASTA formatted sequence
1:	METTPLNSQK QLSACEDGED CQENGVLQKV VPTPGDKVES GQISNGYSAV PSPGAGDDTR 
61:	HSIPATTTTL VAELHQGERE TWGKKVDFLL SVIGYAVDLG NVWRFPYICY QNGGGAFLLP 
121:	YTIMAIFGGI PLFYMELALG QYHRNGCISI WRKICPIFKG IGYAICIIAF YIASYYNTIM 
181:	AWALYYLISS FTDQLPWTSC KNSWNTGNCT NYFSEDNITW TLHSTSPAEE FYTRHVLQIH 
241:	RSKGLQDLGG ISWQLALCIM LIFTVIYFSI WKGVKTSGKV VWVTATFPYI ILSVLLVRGA 
301:	TLPGAWRGVL FYLKPNWQKL LETGVWIDAA AQIFFSLGPG FGVLLAFASY NKFNNNCYQD 
361:	ALVTSVVNCM TSFVSGFVIF TVLGYMAEMR NEDVSEVAKD AGPSLLFITY AEAIANMPAS 
421:	TFFAIIFFLM LITLGLDSTF AGLEGVITAV LDEFPHVWAK RRERFVLAVV ITCFFGSLVT 
481:	LTFGGAYVVK LLEEYATGPA VLTVALIEAV AVSWFYGITQ FCRDVKEMLG FSPGWFWRIC 
541:	WVAISPLFLL FIICSFLMSP PQLRLFQYNY PYWSIILGYC IGTSSFICIP TYIAYRLIIT 
601:	PGTFKERIIK SITPETPTEI PCGDIRLNAV