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Nature May 2019The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons. Major...
The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons. Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors-small molecules that competitively block substrate binding and thereby prolong neurotransmitter action. The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines, and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder. Studies of bacterial NSS homologues-including LeuT-have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane. However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors. Here we report cryo-electron microscopy structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition.
Topics: Binding Sites; Binding, Competitive; Biological Transport; Cryoelectron Microscopy; Hallucinogens; Humans; Ibogaine; Models, Molecular; Protein Conformation; Serotonin; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors; Structure-Activity Relationship
PubMed: 31019304
DOI: 10.1038/s41586-019-1135-1 -
Cell May 2023The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and...
The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine's promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects.
Topics: Animals; Mice; Fluoxetine; Ibogaine; Molecular Conformation; Serotonin; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors; Small Molecule Libraries
PubMed: 37137306
DOI: 10.1016/j.cell.2023.04.010 -
Biochemical Pharmacology Sep 2023Post-translational modifications are an important mechanism in the regulation of protein expression, function, and degradation. Well-known post-translational... (Review)
Review
Post-translational modifications are an important mechanism in the regulation of protein expression, function, and degradation. Well-known post-translational modifications are phosphorylation, glycosylation, and ubiquitination. However, lipid modifications, including myristoylation, prenylation, and palmitoylation, are poorly studied. Since the early 2000s, researchers have become more interested in lipid modifications, especially palmitoylation. The number of articles in PubMed increased from about 350 between 2000 and 2005 to more than 600 annually during the past ten years. S-palmitoylation, where the 16-carbon saturated (C16:0) palmitic acid is added to free cysteine residues of proteins, is a reversible protein modification that can affect the expression, membrane localization, and function of the modified proteins. Various diseases like Huntington's and Alzheimer's disease have been linked to changes in protein palmitoylation. In humans, the addition of palmitic acid is mediated by 23 palmitoyl acyltransferases, also called DHHC proteins. The modification can be reversed by a few thioesterases or hydrolases. Numerous soluble and membrane-attached proteins are known to be palmitoylated, but among the approximately 400 solute carriers that are classified in 66 families, only 15 found in 8 families have so far been documented to be palmitoylated. Among the best-characterized transporters are the glucose transporters GLUT1 (SLC2A1) and GLUT4 (SLC2A4), the three monoamine transporters norepinephrine transporter (NET; SLC6A2), dopamine transporter (DAT; SLC6A3), and serotonin transporter (SERT; SLC6A4), and the sodium-calcium exchanger NCX1 (SLC8A1). While there is evidence from recent proteomics experiments that numerous solute carriers are palmitoylated, no details beyond the 15 transporters covered in this review are available.
Topics: Humans; Palmitic Acid; Lipoylation; Protein Processing, Post-Translational; Phosphorylation; Membrane Proteins; Serotonin Plasma Membrane Transport Proteins
PubMed: 37481134
DOI: 10.1016/j.bcp.2023.115695 -
Nature Metabolism Aug 2023Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by...
Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.
Topics: Humans; Mice; Animals; Adipose Tissue, Brown; Serotonin; Sertraline; Serotonin Plasma Membrane Transport Proteins; Obesity; Thermogenesis; Metabolic Diseases
PubMed: 37537371
DOI: 10.1038/s42255-023-00839-2 -
International Journal of Molecular... Dec 2022Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal disorder characterized by periods of activity and remission. IBD includes Crohn's disease (CD) and... (Review)
Review
Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal disorder characterized by periods of activity and remission. IBD includes Crohn's disease (CD) and ulcerative colitis (UC), and even though IBD has not been considered as a heritable disease, there are genetic variants associated with increased risk for the disease. 5-Hydroxytriptamine (5-HT), or serotonin, exerts a wide range of gastrointestinal effects under both normal and pathological conditions. Furthermore, Serotonin Transporter (SERT) coded by Solute Carrier Family 6 Member 4 () gene (located in the 17q11.1-q12 chromosome), possesses genetic variants, such as Serotonin Transporter Gene Variable Number Tandem Repeat in Intron 2 (STin2-VNTR) and Serotonin-Transporter-linked promoter region (5-HTTLPR), which have an influence over the functionality of SERT in the re-uptake and bioavailability of serotonin. The intestinal microbiota is a crucial actor in normal human gut physiology, exerting effects on serotonin, SERT function, and inflammatory processes. As a consequence of abnormal serotonin signaling and SERT function under these inflammatory processes, the use of selective serotonin re-uptake inhibitors (SSRIs) has been seen to improve disease activity and extraintestinal manifestations, such as depression and anxiety. The aim of this study is to integrate scientific data linking the intestinal microbiota as a regulator of gut serotonin signaling and re-uptake, as well as its role in the pathogenesis of IBD. We performed a narrative review, including a literature search in the PubMed database of both review and original articles (no date restriction), as well as information about the gene and its genetic variants obtained from the Ensembl website. Scientific evidence from in vitro, in vivo, and clinical trials regarding the use of selective serotonin reuptake inhibitors as an adjuvant therapy in patients with IBD is also discussed. A total of 194 articles were used between reviews, in vivo, in vitro studies, and clinical trials.
Topics: Humans; Serotonin; Serotonin Plasma Membrane Transport Proteins; Dysbiosis; Inflammatory Bowel Diseases; Selective Serotonin Reuptake Inhibitors; Immunity
PubMed: 36555276
DOI: 10.3390/ijms232415632 -
Molecular Psychiatry Jan 2022Brain imaging techniques enable the visualization of serotonin transporter (SERT) occupancy as a measure of the proportion of SERT blocked by an antidepressant at a... (Review)
Review
Brain imaging techniques enable the visualization of serotonin transporter (SERT) occupancy as a measure of the proportion of SERT blocked by an antidepressant at a given dose. We aimed to systematically review the evidence on the relationship between antidepressant dose and SERT occupancy. We searched PubMed and Embase (last search 20 May 2021) for human in vivo, within-subject PET, or SPECT studies measuring SERT occupancy at any dose of any antidepressant with highly selective radioligands ([C]-DASB, [I]-ADAM, and [C]-MADAM). We summarized and visualized the dose-occupancy relationship for antidepressants across studies, overlaying the plots with a curve based on predicted values of a standard 2-parameter Michaelis-Menten model fitted using the observed data. We included seventeen studies of 10 different SSRIs, SNRIs, and serotonin modulators comprising a total of 294 participants, involving 309 unique occupancy measures. Overall, following the Michaelis-Menten equation, SERT occupancy increased with a higher dose in a hyperbolic relationship, with occupancy increasing rapidly at lower doses and reaching a plateau at approximately 80% at the usual minimum recommended dose. All the studies were small, only a few investigated the same antidepressant, dose, and brain region, and few reported information on factors that may influence SERT occupancy. The hyperbolic dose-occupancy relationship may provide mechanistic insight of relevance to the limited clinical benefit of dose-escalation in antidepressant treatment and the potential emergence of withdrawal symptoms. The evidence is limited by non-transparent reporting, lack of standardized methods, small sample sizes, and short treatment duration. Future studies should standardize the imaging and reporting procedures, measure occupancy at lower antidepressant doses, and investigate the moderators of the dose-occupancy relationship.
Topics: Antidepressive Agents; Brain; Citalopram; Humans; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 34548628
DOI: 10.1038/s41380-021-01285-w -
ELife Jun 2018A simple label-free method uses the electrical properties of cells to detect how ligands bind to membrane proteins.
A simple label-free method uses the electrical properties of cells to detect how ligands bind to membrane proteins.
Topics: Biophysical Phenomena; Ligands; Membrane Glycoproteins; Membrane Proteins; Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins
PubMed: 29877799
DOI: 10.7554/eLife.37910 -
Scientific Reports Apr 2021Quantifying variation in behaviour-related genes provides insight into the evolutionary potential of repeatable among-individual variation in behaviour (i.e....
Quantifying variation in behaviour-related genes provides insight into the evolutionary potential of repeatable among-individual variation in behaviour (i.e. personality). Yet, individuals typically also plastically adjust their behaviour in response to environmental conditions and/or age, thereby complicating the detection of genotype-phenotype associations. Here, using a population of free-living great tits (Parus major), we assessed the association between single nucleotide polymorphisms (SNPs) in the serotonin transporter gene (SERT) and two repeatable behavioural traits, i.e. female-female aggression and female hissing behaviour. For female-female aggression, a trait showing age-related plasticity, we found no evidence for associations with SERT SNPs, even when assessing potential age-dependent effects of SERT genotype on aggression. We also found no strong support for associations between SERT SNPs and hissing behaviour, yet we identified two synonymous polymorphisms (exon 13 SNP66 and exon 12 SNP144) of particular interest, each explaining about 1.3% of the total variation in hissing behaviour. Overall, our results contribute to the general understanding of the biological underpinning of complex behavioural traits and will facilitate further (meta-analytic) research on behaviour-related genes. Moreover, we emphasize that future molecular genetic studies should consider age-dependent genotype-phenotype associations for behavioural trait (co)variation, as this will vastly improve our understanding of the proximate causes and ultimate consequences of personality variation in natural populations.
Topics: Animals; Behavior, Animal; Female; Gene Frequency; Genetic Association Studies; Passeriformes; Personality; Polymorphism, Single Nucleotide; Serotonin Plasma Membrane Transport Proteins
PubMed: 33883685
DOI: 10.1038/s41598-021-88225-4 -
Advances in Neurobiology 2023Monoamine transporters (MATs) are targets of a wide range of compounds that have been developed as therapeutic treatments for various neuropsychiatric and... (Review)
Review
Monoamine transporters (MATs) are targets of a wide range of compounds that have been developed as therapeutic treatments for various neuropsychiatric and neurodegenerative disorders such as depression, ADHD, neuropathic pain, anxiety disorders, stimulant use disorders, epilepsy, and Parkinson's disease. The MAT family is comprised of three main members - the dopamine transporter (DAT), the norepinephrine transporter (NET), and the serotonin transporter (SERT). These transporters are through reuptake responsible for the clearance of their respective monoamine substrates from the extracellular space. The determination of X-ray crystal structures of MATs and their homologues bound with various substrates and ligands has resulted in a surge of structure-function-based studies of MATs to understand the molecular basis of transport function and the mechanism of various ligands that ultimately result in their behavioral effects. This review focusses on recent examples of ligand-based structure-activity relationship studies trying to overcome some of the challenges associated with previously developed MAT inhibitors. These studies have led to the discovery of unique and novel structurally diverse MAT ligands including allosteric modulators. These novel molecular scaffolds serve as leads for designing more effective therapeutic interventions by modulating the activities of MATs and ultimately their associated neurotransmission and behavioral effects.
Topics: Humans; Biological Transport; Ligands; Serotonin Plasma Membrane Transport Proteins; Vesicular Monoamine Transport Proteins; Mental Disorders; Drug Discovery
PubMed: 36928847
DOI: 10.1007/978-3-031-21054-9_4 -
Saudi Medical Journal May 2018To assess the possible correlation between serotonin and serotonin transporter (SERT) with the autism severity and investigate the association between these parameters...
OBJECTIVES
To assess the possible correlation between serotonin and serotonin transporter (SERT) with the autism severity and investigate the association between these parameters in autistic children to assess their possible role for diagnosis of autism severity.
METHODS
A comparative cross-sectional study was carried out in the Chemistry and Biochemistry Department, College of Medicine, Al-Nahrain University, Baghdad, Iraq while the samples were taken from 60 male autistic children recruited to the Department of Pediatrics at Al-Sader Hospital, Baghdad, Iraq between November 2014 amd April 2015. Levels of serotonin and serotonin transporters (SERT) were determined in 60 male autistic Iraqi patients classified into mild, moderate and severe (20 for each). These levels were compared with those of 26 healthy control children. Results: Levels of serotonin and SERT were significantly increased in autistic children than that of gender and age-matched controls. Serotonin levels were 80.63± 21.83 ng/ml in mild, 100.39±23.07 ng/ml moderate, and 188.7±31.72 ng/ml severe autistic patients. Serotonin transporter levels were 10.13±4.51 ng/ml in mild, 13.15±4.71 ng/ml moderate, and 16.32±6.7 ng/ml in severe autistic patients. The increase of both serotonin and SERT levels were associated with severity of autism. Receiver operating characteristic (ROC) analysis can be used for diagnostic and prognostic purposes.
CONCLUSIONS
High serotonin and SERT levels may indicate that these biomarkers have a role in the autism pathogenesis and support the possibility of using serotonin and SERT to diagnose autism severity.
Topics: Adolescent; Autistic Disorder; Biomarkers; Case-Control Studies; Child; Cross-Sectional Studies; Female; Humans; Male; Serotonin; Serotonin Plasma Membrane Transport Proteins; Severity of Illness Index
PubMed: 29738009
DOI: 10.15537/smj.2018.5.21751