Dopamine Transport by the Serotonin Transporter: A Mechanistically Distinct Mode of Substrate Translocation

The serotonin transporter (SERT) is the principal mechanism for terminating serotonin (5-HT) signals in the nervous system and is a site of action for a variety of psychoactive drugs including antidepressants, amphetamines, and cocaine. Here we show that human SERTs (hSERTs) and rat SERTs are capable of robust dopamine (DA) uptake through a process that differs mechanistically from 5-HT transport in several unanticipated ways. DA transport by hSERT has a higher maximum velocity than 5-HT transport, requires significantly higher Na+ and Cl− concentrations to sustain transport, is inhibited noncompetitively by 5-HT, and is more sensitive to SERT inhibitors, including selective serotonin reuptake inhibitors. We use a thiol-reactive methane thiosulfonate (MTS) reagent to modify a conformationally sensitive cysteine residue to demonstrate that hSERT spends more time in an outward facing conformation when transporting DA than when transporting 5-HT. Cotransfection of an inactive or an MTS-sensitive SERT with wild-type SERT subunits reveals an absence of cooperative interactions between subunits during DA but not 5-HT transport. To establish the physiological relevance of this mechanism for DA clearance, we show using in vivo high-speed chronoamperometry that SERT has the capacity to clear extracellularly applied DA in the hippocampal CA3 region of anesthetized rats. Together, these observations suggest the possibility that SERT serves as a DA transporter in vivo and highlight the idea that there can be distinct modes of transport of alternative physiological substrates by SERT.

• Publication year

  2011

• Venue

  Journal of Neuroscience

• Publication date

  2011-04-27

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1523/JNEUROSCI.0576-11.2011PMID 21525301PMCID PMC3107525
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Structural Analysis of the Extracellular Entrance to the Serotonin Transporter Permeation Pathway*

  2010cited by this paper
• Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy.

  2009cited by this paper
• The mechanism of a neurotransmitter:sodium symporter--inward release of Na+ and substrate is triggered by substrate in a second binding site.

  2008cited by this paper
• Binding of serotonin to the human serotonin transporter. Molecular modeling and experimental validation.

  2008cited by this paper
• Currents in Response to Rapid Concentration Jumps of Amphetamine Uncover Novel Aspects of Human Dopamine Transporter Function

  2008influential reference
• Using High-Speed Chronoamperometry with Local Dopamine Application to Assess Dopamine Transporter Function -- Electrochemical Methods for Neuroscience

  2007cited by this paper
• Ibogaine, a Noncompetitive Inhibitor of Serotonin Transport, Acts by Stabilizing the Cytoplasm-facing State of the Transporter*

  2007cited by this paper
• Mechanism of chloride interaction with neurotransmitter:sodium symporters

  2007cited by this paper
• Identification of a chloride ion binding site in Na+/Cl−-dependent transporters

  2007cited by this paper
• The promiscuity of the dopamine transporter: implications for the kinetic analysis of [3H]serotonin uptake in rat hippocampal and striatal synaptosomes.

  2007cited by this paper
• Serotonin Transporters – Structure and Function

  2006cited by this paper
• Aberrant accumulation of serotonin in dopaminergic neurons.

  2006cited by this paper
• Reuptake of L-DOPA-derived extracellular dopamine in the striatum with dopaminergic denervation via serotonin transporters.

  2006cited by this paper
• The Cytoplasmic Substrate Permeation Pathway of Serotonin Transporter*

  2006cited by this paper
• Differences in the in vivo dynamics of neurotransmitter release and serotonin uptake after acute para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine revealed by chronoamperometry.

  2005cited by this paper
• In vivo electrochemical measurements of serotonin clearance in rat striatum: effects of neonatal 6-hydroxydopamine-induced serotonin hyperinnervation and serotonin uptake inhibitors

  2005cited by this paper
• Corelease of dopamine and serotonin from striatal dopamine terminals.

  2005cited by this paper
• Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters

  2005influential reference
• Temperature and 3,4-methylenedioxymethamphetamine alter human serotonin transporter-mediated dopamine uptake.

  2004cited by this paper
• Dopamine reuptake by norepinephrine neurons: exception or rule?

  2004cited by this paper
• Binding and Transport in Norepinephrine Transporters REAL-TIME, SPATIALLY RESOLVED ANALYSIS IN SINGLE CELLS USING A FLUORESCENT SUBSTRATE*

  2003cited by this paper
• Chemical Modification Strategies for Structure‐Function Studies

  2003cited by this paper
• Binding and Transport in Norepinephrine Transporters

  2003cited by this paper
• Ultrastructural immunocytochemical localization of the dopamine D2 receptor and tyrosine hydroxylase in the rat ventral pallidum

  2002cited by this paper
• Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative.

  2002cited by this paper
• Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference

  2001cited by this paper
• Long distance signalling in volume transmission. Focus on clearance mechanisms.

  2000cited by this paper
• Immunolocalization of the cocaine‐ and antidepressant‐sensitive l‐norepinephrine transporter

  2000cited by this paper
• Oligomerization of serotonin transporter and its functional consequences.

  2000influential reference
• In vivo dopamine clearance rate in rat striatum: regulation by extracellular dopamine concentration and dopamine transporter inhibitors.

  1999cited by this paper
• Differential polarization of serotonin transporters in axons versus soma-dendrites: an immunogold electron microscopy study.

  1999cited by this paper
• Involvement of the Pallidal‐thalamocortical Circuit in Adaptive Behavior

  1999cited by this paper
• Transmembrane Domain I Contributes to the Permeation Pathway for Serotonin and Ions in the Serotonin Transporter

  1999cited by this paper
• Volume transmission in the CNS and its relevance for neuropsychopharmacology.

  1999cited by this paper
• Paracrine neurotransmission in the CNS: involvement of 5-HT.

  1999cited by this paper
• Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system.

  1998cited by this paper
• High Affinity Recognition of Serotonin Transporter Antagonists Defined by Species-scanning Mutagenesis

  1998influential reference
• In vivo chronoamperometric measures of extracellular serotonin clearance in rat dorsal hippocampus: contribution of serotonin and norepinephrine transporters.

  1998cited by this paper
• Dopamine Axon Varicosities in the Prelimbic Division of the Rat Prefrontal Cortex Exhibit Sparse Immunoreactivity for the Dopamine Transporter

  1998cited by this paper
• Pharmacological profile of antidepressants and related compounds at human monoamine transporters.

  1997cited by this paper
• Multiple Ionic Conductances of the Human Dopamine Transporter: The Actions of Dopamine and Psychostimulants

  1997cited by this paper
• The Dopamine Transporter: Comparative Ultrastructure of Dopaminergic Axons in Limbic and Motor Compartments of the Nucleus Accumbens

  1997cited by this paper
• The Third Transmembrane Domain of the Serotonin Transporter Contains Residues Associated with Substrate and Cocaine Binding*

  1997influential reference
• Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites.

  1997cited by this paper
• Immunocytochemical detection of the serotonin transporter in rat brain.

  1996cited by this paper
• Dopamine transporter immunohistochemistry in median eminence, amygdala, and other areas of the rat brain

  1996cited by this paper
• In Vivo Assessment of Dopamine Uptake in Rat Medial Prefrontal Cortex: Comparison with Dorsal Striatum and Nucleus Accumbens

  1995cited by this paper
• Dynamics of 5-hydroxytryptamine released from dopamine neurons in the caudate putamen of the rat.

  1995cited by this paper
• The dopamine transporter: immunochemical characterization and localization in brain

  1995cited by this paper
• Ligand binding to the serotonin transporter: equilibria, kinetics, and ion dependence.

  1994cited by this paper
• A cocaine-sensitive Drosophila serotonin transporter: cloning, expression, and electrophysiological characterization.

  1994cited by this paper
• Clearance of Exogenous Dopamine in Rat Dorsal Striatum and Nucleus Accumbens: Role of Metabolism and Effects of Locally Applied Uptake Inhibitors

  1993cited by this paper
• Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization.

  1993cited by this paper
• Ultrastructure of serotonin‐immunoreactive terminals in the core and shell of the rat nucleus accumbens: Cellular substrates for interactions with catecholamine afferents

  1993cited by this paper
• Cloning of a serotonin transporter affected by antidepressants.

  1991cited by this paper
• Striatal dopamine terminals release serotonin after 5-HTP pretreatment: in vivo voltammetric data.

  1990cited by this paper
• Evidence that [3H]Dopamine Is Taken Up and Released from Nondopaminergic Nerve Terminals in the Rat Substantia Nigra In Vitro

  1985cited by this paper
• Morphological evidence for a dopaminergic terminal field in the hippocampal formation of young and adult rat.

  1985cited by this paper
• The Rat Brain in Stereotaxic Coordinates

  1983influential reference
• AChE-stained horizontal sections of the rat brain in stereotaxic coordinates.

  1980cited by this paper
• Dopamine uptake in serotoninergic terminals in vitro: a valuable tool for the histochemical differentiation of catecholaminergic and serotoninergic terminals in rat cerebral structures.

  1978cited by this paper
• Enzyme kinetics: Behavior and analysis of rapid equilibrium and steady‐state enzyme systems. Author: Irwin H. Segal (University of California, Davis). Published by Wiley‐Interscience, New York, 1975. Price: $24.50. No. of pages: 957

  1976cited by this paper
• Selectivity of release of norepinephrine, dopamine and 5-hydroxytryptamine by amphetamine in various regions of rat brain.

  1973cited by this paper

• ASTROGLIA: Molecular Mechanisms, Functional Roles, and Neurophysiological Implications in the Central Nervous System

  2025cites this paper
• Dopamine and serotonin cotransmission filters striatonigral synaptic activity via 5-HT1B receptor activation

  2025cites this paper
• Substrate Binding and Conformational Dynamics of the Monoamine Transporters.

  2025cites this paper
• Estrogen modulates reward prediction errors and reinforcement learning

  2025cites this paper
• Fluorescent non-canonical amino acid provides insight into the human serotonin transporter

  2024cites this paper
• Effects of genetic knockdown of the serotonin transporter on established L-DOPA-induced dyskinesia and gene expression in hemiparkinsonian rats.

  2024cites this paper
• The nucleus accumbens in reward and aversion processing: insights and implications

  2024cites this paper
• Oligomerization of Monoamine Transporters.

  2024cites this paper
• Serotonergic Regulation of Synaptic Dopamine Levels Mitigates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson’s Disease

  2024cites this paper
• Alterations in Serotonin Neurotransmission in Hyperdopaminergic Rats Lacking the Dopamine Transporter

  2023cites this paper
• Striatal serotonin transporter gain-of-function in L-DOPA-treated, hemi-parkinsonian rats.

  2023cites this paper
• Persistent binding at dopamine transporters determines sustained psychostimulant effects

  2023cites this paper
• A narrative review of the neuropharmacology of synthetic cathinones—Popular alternatives to classical drugs of abuse

  2023cites this paper
• Histone H3 dopaminylation in nucleus accumbens, but not medial prefrontal cortex, contributes to cocaine-seeking following prolonged abstinence.

  2023cites this paper
• Overview of the structure and function of the dopamine transporter and its protein interactions

  2023cites this paper
• Estrogenic control of reward prediction errors and reinforcement learning

  2023cites this paper
• Chirality Matters: Fine-Tuning of Novel Monoamine Reuptake Inhibitors Selectivity through Manipulation of Stereochemistry

  2023cites this paper
• Functional characterization of dopamine and norepinephrine transport across the apical and basal plasma membranes of the human placental syncytiotrophoblast

  2022cites this paper
• 5-HTR2B and SLC6A3 as potential molecular targets of sertraline in the treatment of major depressive disorder: the use of bioinformatics and its practical implication

  2022cites this paper
• The effects of Vilazodone, YL-0919 and Vortioxetine in hemiparkinsonian rats

  2022cites this paper
• In Silico Investigations into the Selectivity of Psychoactive and New Psychoactive Substances in Monoamine Transporters

  2022cites this paper
• Consequences of Acute or Chronic Methylphenidate Exposure Using Ex Vivo Neurochemistry and In Vivo Electrophysiology in the Prefrontal Cortex and Striatum of Rats

  2022cites this paper
• A New Method for the Visualization of Living Dopaminergic Neurons and Prospects for Using It to Develop Targeted Drug Delivery to These Cells

  2022cites this paper
• Serotonin receptors contribute to dopamine depression of lateral inhibition in the nucleus accumbens

  2022cites this paper
• Current understanding of the genetics of tourette syndrome

  2022cites this paper
• Candidate Genes and Pathways Associated with Gilles de la Tourette Syndrome—Where Are We?

  2021cites this paper
• Psychomotor stimulant effects of α-pyrrolidinovalerophenone (αPVP) enantiomers correlate with drug binding kinetics at the dopamine transporter

  2021cites this paper
• A model of dopamine and serotonin-kynurenine metabolism in cortisolemia: Implications for depression

  2021cites this paper
• Elevated Expression of SLC6A4 Encoding the Serotonin Transporter (SERT) in Gilles de la Tourette Syndrome

  2021cites this paper
• Levels of dopamine, 5-hydroxytryptamine and their metabolites in the striatum of rats of various strains receiving a high-calorie diet

  2021cites this paper
• Role of 5-HT1A Receptor in Vilazodone-Mediated Suppression of L-DOPA-Induced Dyskinesia and Increased Responsiveness to Cortical Input in Striatal Medium Spiny Neurons in an Animal Model of Parkinson’s Disease

  2021cites this paper
• Illumination of serotonin transporter mechanism and role of the allosteric site

  2021cites this paper
• Constitutive depletion of brain serotonin differentially affects rats’ social and cognitive abilities

  2021cites this paper
• Synergistic Effect of Serotonin 1A and Serotonin 1B/D Receptor Agonists in the Treatment of L-DOPA-Induced Dyskinesia in 6-Hydroxydopamine-Lesioned Rats

  2021cites this paper
• Comparative neuropharmacological studies on three pyrrolidine-containing synthetic cathinones

  2020cites this paper
• Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy

  2020cites this paper
• Understanding the Contribution of Individual Amino Acid Residues in the Binding of Psychoactive Substances to Monoamine Transporters

  2020cites this paper
• Quantifying secondary transport at single-molecule resolution

  2019cites this paper
• Age- and Sex-Specific Plasticity in Dopamine Transporter Function Revealed by Food Restriction and Exercise in a Rat Activity-Based Anorexia Paradigm

  2019cites this paper
• Concurrent Inhibition of Vesicular Monoamine Transporter 2 Does Not Protect Against 3,4-Methylenedioxymethamphetamine (Ecstasy) Induced Neurotoxicity.

  2019cites this paper
• Monoamine transporters: structure, intrinsic dynamics and allosteric regulation

  2019cites this paper
• Investigating the anti-cocaine, anti-nociceptive properties and side effects of MP1104, a novel mixed opioid receptor agonist

  2019cites this paper
• Serotonergic targets for the treatment of l-DOPA-induced dyskinesia

  2018cites this paper
• Methcathinone and 3-Fluoromethcathinone Stimulate Spontaneous Horizontal Locomotor Activity in Mice and Elevate Extracellular Dopamine and Serotonin Levels in the Mouse Striatum

  2018cites this paper
• Diverse serotonin actions of vilazodone reduce l‐3,4‐dihidroxyphenylalanine–induced dyskinesia in hemi‐parkinsonian rats

  2018cites this paper
• Simultaneous Detection of Dopamine and Serotonin—A Comparative Experimental and Theoretical Study of Neurotransmitter Interactions

  2018cites this paper
• Computational models of dopamine diffusion and receptor binding in the striatum

  2018cites this paper
• Interactions of the tricyclic antidepressant drug amitriptyline with L‐DOPA in the striatum and substantia nigra of unilaterally 6‐OHDA‐lesioned rats. Relevance to motor dysfunction in Parkinson's disease

  2018cites this paper
• Effects of the new generation α-pyrrolidinophenones on spontaneous locomotor activities in mice, and on extracellular dopamine and serotonin levels in the mouse striatum

  2018cites this paper
• Effects of Synthetic Cathinones on Brain Neurotransmitters

  2018cites this paper
• Functional properties of dopamine transporter oligomers after copper linking

  2018cites this paper
• 3D similarities between the binding sites of monoaminergic target proteins

  2018cites this paper
• Expanding the repertoire of L-DOPA's actions: A comprehensive review of its functional neurochemistry.

  2017cites this paper
• Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications

  2017cites this paper
• Noradrenergic modulation of evoked dopamine release and pH shift in the mouse dorsal hippocampus and ventral striatum.

  2017cites this paper
• Pharmacological Chaperones of the Dopamine Transporter: A Strategy for Increasing Function of Wild Type and Mutant Transporter

  2017cites this paper
• Enhanced dopamine detection sensitivity by PEDOT/graphene oxide coating on in vivo carbon fiber electrodes.

  2017cites this paper
• Cocaine-Induced Metaplasticity in the CA1 Region of the Hippocampus

  2017cites this paper
• Milnacipran affects mouse impulsive, aggressive, and depressive-like behaviors in a distinct dose-dependent manner.

  2017cites this paper
• L-DOPA elicits non-vesicular releases of serotonin and dopamine in hemiparkinsonian rats in vivo.

  2016cites this paper
• Modelling Cellular Permeability via Carrier Mediated Transport

  2016cites this paper
• Antiparkinsonian Treatment for Depression in Parkinson's Disease: Are Selective Serotonin Reuptake Inhibitors Recommended?

  2016cites this paper
• What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?

  2016cites this paper
• Adaptive down-regulation of the serotonin transporter in the 6-hydroxydopamine-induced rat model of preclinical stages of Parkinson's disease and after chronic pramipexole treatment.

  2016cites this paper
• Immunomodulatory Effects Mediated by Dopamine

  2016cites this paper
• Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters

  2016cites this paper
• Effect of tricyclic antidepressants on L-DOPA-induced dyskinesia and motor improvement in hemi-parkinsonian rats.

  2016cites this paper
• Substrate-induced Unlocking of the Inner Gate Determines the Catalytic Efficiency of a Neurotransmitter:Sodium Symporter*

  2015cites this paper
• Role of organic cation transporters (OCTs) in the brain.

  2015cites this paper
• Presynaptic effects of levodopa and their possible role in dyskinesia

  2015cites this paper
• Visual hallucinations: a treatment-emergent adverse effect of linezolid.

  2015cites this paper
• Eating High Fat Chow Decreases Dopamine Clearance in Adolescent and Adult Male Rats but Selectively Enhances the Locomotor Stimulating Effects of Cocaine in Adolescents

  2015cites this paper
• REGULATION OF DENDRITIC SPINES BY 5-HT2A RECEPTOR SIGNALING PATHWAYS

  2015cites this paper
• Leveraging the occurrence of spontaneous D2 receptor-mediated IPSCs to understand the dopamine synapse

  2015influential citation
• Dopamine transporter oligomerization: impact of combining protomers with differential cocaine analog binding affinities

  2015cites this paper
• SERT and NET polymorphisms, temperament and antidepressant response

  2015cites this paper
• Monoamine transporters: insights from molecular dynamics simulations

  2015cites this paper
• Serotonylation and Transamidation of Other Monoamines.

  2015cites this paper
• melanogaster as a genetic model system to study neurotransmitter transporters

  2014cites this paper
• Structure, function, and plasticity of GABA transporters

  2014cites this paper
• Increased DAT binding in the early stage of the dopaminergic lesion: A longitudinal [11C]PE2I binding study in the MPTP-monkey

  2014cites this paper
• Serotonergic nerve fibers in L-DOPA-derived dopamine release and dyskinesia.

  2014cites this paper
• Drosophila melanogaster as a genetic model system to study neurotransmitter transporters.

  2014cites this paper
• Effects of prolonged selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemi-parkinsonian rats.

  2014cites this paper
• In vivo fast scan cyclic voltammetry reveals that restricted diffusion maintains discrete dopamine domains in the dorsal striatum

  2014cites this paper
• Effects of dopaminergic system activation on feeding behavior and growth performance of the sea bass (Dicentrarchus labrax): a self-feeding approach.

  2013cites this paper
• Identification of an allosteric modulator of the serotonin transporter with novel mechanism of action.

  2013cites this paper
• Comparative modeling of the human monoamine transporters: similarities in substrate binding.

  2013cites this paper
• Dysfunction in the nigrostriatal system : effects of L-DOPA and GDNF

  2013cites this paper
• Sensation‐seeking genes and physical activity in youth

  2013cites this paper
• Multisite intracerebral microdialysis to study the mechanism of L-DOPA induced dopamine and serotonin release in the parkinsonian brain.

  2013cites this paper
• Kinetics of the dopamine transporter in Drosophila larva.

  2013cites this paper
• Extracellular loop 3 of the noradrenaline transporter contributes to substrate and inhibitor selectivity

  2013cites this paper
• Advances in studying phasic dopamine signaling in brain reward mechanisms.

  2013cites this paper
• Immunity on Dendritic Cells Potentiates Th17-Mediated Stimulation of Dopamine Receptor D5 Expressed

  2012cites this paper
• The solute carrier 6 family of transporters

  2012cites this paper
• Psychiatric drugs bind to classical targets within early exocytotic pathways: therapeutic effects.

  2012cites this paper
• Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

  2012cites this paper
• Dopamine Transporter Loss in 6-OHDA Parkinson’s Model Is Unmet by Parallel Reduction in Dopamine Uptake

  2012cites this paper
• You are what you eat: influence of type and amount of food consumed on central dopamine systems and the behavioral effects of direct- and indirect-acting dopamine receptor agonists.

  2012cites this paper