Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Monoamine transporters: vulnerable and vital doorkeepers.

ABSTRACT: Transporters of dopamine, serotonin, and norepinephrine have been empirically used as medication targets for several mental illnesses in the last decades. These protein-targeted medications are effective only for subpopulations of patients with transporter-related brain disorders. Since the cDNA clonings in early 1990s, molecular studies of these transporters have revealed a wealth of information about the transporters' structure-activity relationship (SAR), neuropharmacology, cell biology, biochemistry, pharmacogenetics, and the diseases related to the human genes encoding these transporters among related regulators. Such new information creates a unique opportunity to develop transporter-specific medications based on SAR, mRNA, DNA, and perhaps transporter trafficking regulation for a number of highly relevant diseases including substance abuse, depression, schizophrenia, and Parkinson's disease.

SUBMITTER: Lin Z

PROVIDER: S-EPMC3321928 | biostudies-other | 2011

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

Monoamine transporters: vulnerable and vital doorkeepers.

Lin Zhicheng Z Canales Juan J JJ Björgvinsson Thröstur T Thomsen Morgane M Qu Hong H Liu Qing-Rong QR Torres Gonzalo E GE Caine S Barak SB

Progress in molecular biology and translational science 20110101

Transporters of dopamine, serotonin, and norepinephrine have been empirically used as medication targets for several mental illnesses in the last decades. These protein-targeted medications are effective only for subpopulations of patients with transporter-related brain disorders. Since the cDNA clonings in early 1990s, molecular studies of these transporters have revealed a wealth of information about the transporters' structure-activity relationship (SAR), neuropharmacology, cell biology, bioc ...[more]

PMID: 21199769

Similar Datasets

Overview of Monoamine Transporters.

Project description:The dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters, which are collectively referred to as monoamine transporters (MATs), play significant roles in regulating the neuronal response to these neurotransmitters. MATs terminate the action of these neurotransmitters by translocating them from the synaptic space into the presynaptic neurons. These three transmitters are responsible for controlling a number of physiological, emotional, and behavioral functions, with their transporters being the site of action of drugs employed for the treatment of a variety of conditions, including depression, anxiety, ADHD, schizophrenia, and psychostimulant abuse. Provided in this unit is information on the localization and regulation of MATs and the structural components of these proteins most responsible for the translocation process. Also included is a brief description of the evolution of ligands that interact with these transporters, as well as current theories concerning the pharmacological effects of substances that interact with these sites, including the molecular mechanisms of action of uptake inhibitors and allosteric modulators. Data relating to the presence, structure, and functions of allosteric modulators are included as well. The aim of this review is to provide background information on MATs to those who are new to this field, with a focus on the therapeutic potential of compounds that interact with these substrate transport sites. © 2017 by John Wiley & Sons, Inc.

| S-EPMC5841473 | biostudies-literature

Chloride requirement for monoamine transporters.

Project description:This review focuses on the Cl(-) requirement for dopamine, serotonin, and norepinephrine (DA, 5-HT, and NE) transport and induced current via the transporters for these transmitters, DAT, SERT, and NET. Indirect evidence exists for the passage of Cl(-) ions through monoamine transporters; however, direct evidence is sparse. An unanswered question is why in some preparations, notably native neurons, it appears that Cl(-) ions carry the current through DAT, whereas in heterologous expression systems Na(+) ions carry the current often referred to as the uncoupled current. It is suggested that different functional states in monoamine transporters represent conformational states that carry dominantly Cl(-) or Na(+). Structures of monoamine transporters contribute enormously to structure-function relationships; however, thus far no structural features support the functionally relevant ionic currents that are known to exist in monoamine transporters.

| S-EPMC4752906 | biostudies-literature

Monoamine transporters: insights from molecular dynamics simulations.

Project description:The human monoamine transporters (MATs) facilitate the reuptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Imbalance in monoaminergic neurotransmission is linked to various diseases including major depression, attention deficit hyperactivity disorder, schizophrenia, and Parkinson's disease. Inhibition of the MATs is thus an important strategy for treatment of such diseases. The MATs are sodium-coupled transport proteins belonging to the neurotransmitter/Na(+) symporter (NSS) family, and the publication of the first high-resolution structure of a NSS family member, the bacterial leucine transporter LeuT, in 2005, proved to be a major stepping stone for understanding this family of transporters. Structural data allows for the use of computational methods to study the MATs, which in turn has led to a number of important discoveries. The process of substrate translocation across the membrane is an intrinsically dynamic process. Molecular dynamics simulations, which can provide atomistic details of molecular motion on ns to ms timescales, are therefore well-suited for studying transport processes. In this review, we outline how molecular dynamics simulations have provided insight into the large scale motions associated with transport of the neurotransmitters, as well as the presence of external and internal gates, the coupling between ion and substrate transport, and differences in the conformational changes induced by substrates and inhibitors.

| S-EPMC4607855 | biostudies-literature

Monoamine transporters: structure, intrinsic dynamics and allosteric regulation.

Project description:Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from extra-neuronal regions and thus maintain neurotransmitter homeostasis. As targets of a wide range of compounds, including antidepressants, substances of abuse and drugs for neuropsychiatric and neurodegenerative disorders, their mechanism of action and their modulation by small molecules have long been of broad interest. Recent advances in the structural characterization of dopamine and serotonin transporters have opened the way for structure-based modeling and simulations, which, together with experimental data, now provide mechanistic understanding of their transport function and interactions. Here we review recent progress in the elucidation of the structural dynamics of MATs and their conformational landscape and transitions, as well as allosteric regulation mechanisms.

| S-EPMC6712983 | biostudies-literature

The ins and outs of vesicular monoamine transporters.

Project description:The H+-coupled vesicular monoamine transporter (VMAT) is a transporter essential for life. VMAT mediates packaging of the monoamines serotonin, dopamine, norepinephrine, and histamine from the neuronal cytoplasm into presynaptic vesicles, which is a key step in the regulated release of neurotransmitters. However, a detailed understanding of the mechanism of VMAT function has been limited by the lack of availability of high-resolution structural data. In recent years, a series of studies guided by homology models has revealed significant insights into VMAT function, identifying residues that contribute to the binding site and to specific steps in the transport cycle. Moreover, to characterize the conformational transitions that occur upon binding of the substrate and coupling ion, we have taken advantage of the unique and powerful pharmacology of VMAT as well as of mutants that affect the conformational equilibrium of the protein and shift it toward defined conformations. This has allowed us to identify an important role for the proton gradient in driving a shift from lumen-facing to cytoplasm-facing conformations.

| S-EPMC5940252 | biostudies-literature

Designing modulators of monoamine transporters using virtual screening techniques.

Project description:The plasma-membrane monoamine transporters (MATs), including the serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective monoamine neurotransmitters. The transporters are the main target of clinically used psychostimulants and antidepressants. Despite the availability of several potent and selective MAT substrates and inhibitors the continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to identify novel ways of targeting and modulating the MATs. Designing novel modulators of MAT function have been limited by the lack of three dimensional structure information of the individual MATs. However, crystal structures of LeuT, a bacterial homolog of MATs, in a substrate-bound occluded, substrate-free outward-open, and an apo inward-open state and also with competitive and non-competitive inhibitors have been determined. In addition, several structures of the Drosophila DAT have also been resolved. Together with computational modeling and experimental data gathered over the past decade, these structures have dramatically advanced our understanding of several aspects of SERT, NET, and DAT transporter function, including some of the molecular determinants of ligand interaction at orthosteric substrate and inhibitor binding pockets. In addition progress has been made in the understanding of how allosteric modulation of MAT function can be achieved. Here we will review all the efforts up to date that has been made through computational approaches employing structural models of MATs to design small molecule modulators to the orthosteric and allosteric sites using virtual screening techniques.

| S-EPMC4586420 | biostudies-literature

An unfolding story: Small molecules remedy misfolded monoamine transporters.

Project description:The key role of monoamine transporters is to take up neurotransmitters from the synaptic cleft and rapidly terminate neurotransmission. Monoamine transporters begin their journey by folding in the endoplasmic reticulum. Upon achieving their natively-folded state, the oligomerized transporters engage the coat protein complex II machinery and exit the endoplasmic reticulum compartment in a concentrative fashion. The transporters are subsequently sorted in the endoplasmic reticulum-Golgi intermediate complex and the Golgi apparatus, prior to reaching their pivotal site of action at the plasma membrane. Stringent quality-control mechanisms ensure that only the correctly-folded protein cargo departs the endoplasmic reticulum. Genetic point mutations in the coding sequences of monoamine transporters can trigger severe physiologic deficiencies by inducing folding defects. Protein misfolding precludes the delivery of functional monoamine transporters to the cell surface. Chemical- and/or pharmacological-chaperone molecules, which facilitate folding, have proven effective in restoring the activity of several misfolded pathological variants of monoamine transporters.

| S-EPMC5679356 | biostudies-literature

Vesicular monoamine and glutamate transporters select distinct synaptic vesicle recycling pathways.

Project description:Previous work has characterized the properties of neurotransmitter release at excitatory and inhibitory synapses, but we know remarkably little about the properties of monoamine release, because these neuromodulators do not generally produce a fast ionotropic response. Since dopamine and serotonin neurons can also release glutamate in vitro and in vivo, we have used the vesicular monoamine transporter VMAT2 and the vesicular glutamate transporter VGLUT1 to compare the localization and recycling of synaptic vesicles that store, respectively, monoamines and glutamate. First, VMAT2 segregates partially from VGLUT1 in the boutons of midbrain dopamine neurons, indicating the potential for distinct release sites. Second, endocytosis after stimulation is slower for VMAT2 than VGLUT1. During the stimulus, however, the endocytosis of VMAT2 (but not VGLUT1) accelerates dramatically in midbrain dopamine but not hippocampal neurons, indicating a novel, cell-specific mechanism to sustain high rates of release. On the other hand, we find that in both midbrain dopamine and hippocampal neurons, a substantially smaller proportion of VMAT2 than VGLUT1 is available for evoked release, and VMAT2 shows considerably more dispersion along the axon after exocytosis than VGLUT1. Even when expressed in the same neuron, the two vesicular transporters thus target to distinct populations of synaptic vesicles, presumably due to their selection of distinct recycling pathways.

| S-EPMC3184447 | biostudies-literature

Comparative modeling of the human monoamine transporters: similarities in substrate binding.

Project description:The amino acid compositions of the substrate binding pockets of the three human monoamine transporters are compared as is the orientation of the endogenous substrates, serotonin, dopamine, and norepinephrine, bound in these. Through a combination of homology modeling, induced fit dockings, molecular dynamics simulations, and uptake experiments in mutant transporters, we propose a common binding mode for the three substrates. The longitudinal axis of the substrates is similarly oriented with these, forming an ionic interaction between the ammonium group and a highly conserved aspartate, Asp98 (serotonin transporter, hSERT), Asp79 (dopamine transporter, hDAT), and Asp75 (norepinephrine transporter, hNET). The 6-position of serotonin and the para-hydroxyl groups of dopamine and norepinephrine were found to face Ala173 in hSERT, Gly153 in hDAT, and Gly149 in hNET. Three rotations of the substrates around the longitudinal axis were identified. In each mode, an aromatic hydroxyl group of the substrates occupied equivalent volumes of the three binding pockets, where small changes in amino acid composition explains the differences in selectivity. Uptake experiments support that the 5-hydroxyl group of serotonin and the meta-hydroxyl group norepinephrine and dopamine are placed in the hydrophilic pocket around Ala173, Ser438, and Thr439 in hSERT corresponding to Gly149, Ser419, Ser420 in hNET and Gly153 Ser422 and Ala423 in hDAT. Furthermore, hDAT was found to possess an additional hydrophilic pocket around Ser149 to accommodate the para-hydroxyl group. Understanding these subtle differences between the binding site compositions of the three transporters is imperative for understanding the substrate selectivity, which could eventually aid in developing future selective medicines.

| S-EPMC3582297 | biostudies-literature

Binding of the amphetamine-like 1-phenyl-piperazine to monoamine transporters.

Project description:The human serotonin transporter (hSERT), the human dopamine transporter (hDAT), and the human norepinephrine transporter (hNET) facilitate the active uptake of the neurotransmitters serotonin, dopamine, and norepinephrine from the synaptic cleft. Drugs of abuse such as MDMA (streetname "ecstasy") and certain 1-phenyl-piperazine (PP) analogs such as 1-(3-chlorophenyl)-piperazine (mCPP) elicit their stimulatory effect by elevating the synaptic concentration of serotonin by blocking or reversing the normal transport activity of hSERT. Recent data suggest that certain analogs of PP may be able to counteract the addictive effect of cocaine. Little is still known about the precise mechanism by which MDMA and PP analogs function at hSERT, hDAT, and hNET and even less is known about the specific protein-ligand interactions. In this study, we provide a comprehensive biochemical examination of a repertoire of PP analogs in hSERT, hDAT, and hNET. Combined with induced fit docking models and molecular dynamics simulations of PP and 1-(3-hydroxyphenyl)-piperazine (3-OH-PP) bound to hSERT and hDAT, we present detailed molecular insight into the promiscuous binding of PP analogs in the monoamine transporters. We find that PP analogs inhibit uptake as well as induce release in all three monoamine transporters. We also find that the selectivity of the PP analogs can be adjusted by carefully selecting substituents on the PP skeleton.

| S-EPMC3447394 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data