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Neurochemistry International Jan 2019The signaling dynamics of the neurotransmitter dopamine has been established to have an important role in a variety of behavioural processes including motor control,... (Review)
Review
The signaling dynamics of the neurotransmitter dopamine has been established to have an important role in a variety of behavioural processes including motor control, cognition, and emotional processing. Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. This review provides an overview of how these transporter proteins are involved in molecular regulation and function together to govern the dynamics of vesicular release with opposing effects on the quantal size and extracellular concentration of dopamine. These transporter proteins are both focal points of convergence for a variety of regulatory molecular cascades as well as targets for many pharmacological agents. The ratio between these transporters is argued to be useful as a molecular marker for delineating dopamine functional subsystems that may differ in transmitter release patterns.
Topics: Animals; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Synaptic Transmission; Synaptic Vesicles; Vesicular Monoamine Transport Proteins
PubMed: 30465801
DOI: 10.1016/j.neuint.2018.11.004 -
International Journal of Molecular... Oct 2021A major goal of current clinical research in Parkinson's disease (PD) is the validation and standardization of biomarkers enabling early diagnosis, predicting outcomes,... (Review)
Review
A major goal of current clinical research in Parkinson's disease (PD) is the validation and standardization of biomarkers enabling early diagnosis, predicting outcomes, understanding PD pathophysiology, and demonstrating target engagement in clinical trials. Molecular imaging with specific dopamine-related tracers offers a practical indirect imaging biomarker of PD, serving as a powerful tool to assess the status of presynaptic nigrostriatal terminals. In this review we provide an update on the dopamine transporter (DAT) imaging in PD and translate recent findings to potentially valuable clinical practice applications. The role of DAT imaging as diagnostic, preclinical and predictive biomarker is discussed, especially in view of recent evidence questioning the incontrovertible correlation between striatal DAT binding and nigral cell or axon counts.
Topics: Animals; Biomarkers; Dopamine Plasma Membrane Transport Proteins; Humans; Molecular Imaging; Parkinson Disease
PubMed: 34681899
DOI: 10.3390/ijms222011234 -
Molecular Nutrition & Food Research Mar 2016The present study aimed to characterize and evaluate flavonoids effects on organic cation uptake in neuronal cells.
SCOPE
The present study aimed to characterize and evaluate flavonoids effects on organic cation uptake in neuronal cells.
METHODS AND RESULTS
Uptake experiments were conducted using radiolabeled methyl-4-phenylpyridinuim ([(3) H]-MPP(+) ), in human neuronal dopaminergic cells, SH-SY5Y. Catechin did not alter [(3) H]-MPP(+) uptake, however its metabolite 4'-methyl-catechin decreased it by almost 50%. Epicatechin and its methylated metabolites also decreased [(3) H]-MPP(+) uptake. Interestingly, the quercetin flavonol and its metabolite conjugated with glucuronic acid, as well as the flavanones naringenin and hesperitin, increased [(3) H]-MPP(+) uptake.
CONCLUSION
These results showed that different classes of flavonoids, as well as its metabolites, differently influence neuronal organic cation uptake. Several xeno- and endobiotics, including neurotransmitters, are organic cations. Specific food recommendations may be beneficial in pathological conditions where levels of neurotransmitters, as dopamine, are either increased or decreased.
Topics: 1-Methyl-4-phenylpyridinium; Cations; Cell Line; Dopamine; Dopamine Plasma Membrane Transport Proteins; Enzyme Inhibitors; Flavonoids; Humans; Neurons; Neurotransmitter Agents; Piperazines; Signal Transduction
PubMed: 26582321
DOI: 10.1002/mnfr.201500557 -
The Journal of Clinical Investigation May 2019The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA...
The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, Autism Spectrum Disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine to methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e. anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous dopamine efflux. Here we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation display impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.
Topics: Amino Acid Substitution; Animals; Autistic Disorder; Behavior, Animal; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drosophila Proteins; Drosophila melanogaster; Mice; Mice, Mutant Strains; Mutation, Missense; Synaptic Transmission
PubMed: 31094705
DOI: 10.1172/JCI127411 -
Parkinsonism & Related Disorders Sep 2023Glymphatic dysfunction can contribute to α-synucleinopathies. We examined glymphatic function in idiopathic Parkinson's disease (PD) utilizing Diffusion Tensor Image...
INTRODUCTION
Glymphatic dysfunction can contribute to α-synucleinopathies. We examined glymphatic function in idiopathic Parkinson's disease (PD) utilizing Diffusion Tensor Image Analysis aLong the Perivascular Space (DTI-ALPS).
METHODS
This study enrolled consecutive patients diagnosed with de novo PD between June 2017 and March 2019 who underwent brain DTI with concurrent I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (I-FP-CIT) SPECT, and age- and sex-matched controls. From DTI-ALPS, the ALPS-index was calculated as a ratio of diffusivities along the x-axis in the region of neural fibers passing vertically to the diffusivities perpendicular to them, which reflected perivascular water motion at the lateral ventricular body level. The ALPS-index of the PD and control groups was compared using Student's t-test; its correlations with clinical scores for motor and cognition (UPDRS-III, MMSE, and MoCA) and striatal dopamine transporter uptake measured by I-FP-CIT specific binding ratios (SBRs) were examined using a correlation coefficient.
RESULTS
In all, 54 patients in the de novo PD group (31 women, 23 men; mean age, 68.9 ± 9.4 years) and 54 in the control group (mean age, 69.0 ± 10.5 years) were included. The ALPS-index was lower in the PD group than in the controls (1.51 ± 0.22 versus 1.66 ± 0.20; P < 0.001). In the PD group, the ALPS-index negatively correlated with the UPDRS-III score (r = -0.526), and positively correlated with the MMSE (r = 0.377) and MoCA scores (r = 0.382) (all, P < 0.05). No correlation was observed between the ALPS-index and striatal I-FP-CIT SBRs (P > 0.05).
CONCLUSIONS
DTI-ALPS can reveal glymphatic dysfunction in patients with PD, whose severity correlated with motor and cognitive dysfunction, but not striatal dopamine transporter uptake.
Topics: Male; Humans; Female; Middle Aged; Aged; Parkinson Disease; Dopamine Plasma Membrane Transport Proteins; Tropanes
PubMed: 37523953
DOI: 10.1016/j.parkreldis.2023.105767 -
Biomolecules Jan 2020The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors of human NET (hNET) play a...
The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors of human NET (hNET) play a major role in the treatment of many central and peripheral nervous system diseases. In this study, we focused on the spatial structure of a NET constructed by homology modeling on dopamine transporter templates. We further examined molecular construction of primary binding pocket (S1) together with secondary binding site (S2) and extracellular loop 4 (EL4). The next stage involved docking of transporter inhibitors: Reboxetine, duloxetine, desipramine, and other commonly used drugs. The procedure revealed the molecular orientation of residues and disclosed ones that are the most important for ligand binding: Phenylalanine F72, aspartic acid D75, tyrosine Y152, and phenylalanine F317. Aspartic acid D75 plays a key role in recognition of the basic amino group present in monoamine transporter inhibitors and substrates. The study also presents a comparison of hNET models with other related proteins, which could provide new insights into their interaction with therapeutics and aid future development of novel bioactive compounds.
Topics: Animals; Binding Sites; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drosophila Proteins; Drosophila melanogaster; Humans; Molecular Dynamics Simulation; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Protein Binding
PubMed: 31936154
DOI: 10.3390/biom10010102 -
The European Journal of Neuroscience Jan 2017Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine... (Review)
Review
Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) are regulators of dopamine homeostasis in the presynaptic neuron. DAT transports dopamine from the extracellular space into the cytosol of the presynaptic terminal. VMAT2 then packages this cytosolic dopamine into vesicular compartments for subsequent release upon neurotransmission. Thus, DAT and VMAT2 act in concert to move the transmitter efficiently throughout the neuron. Accumulation of dopamine in the neuronal cytosol can trigger oxidative stress and neurotoxicity, suggesting that the proper compartmentalization of dopamine is critical for neuron function and risk of disease. For decades, studies have examined the effects of reduced transporter function in mice (e.g. DAT-KO, VMAT2-KO, VMAT2-deficient). However, we have only recently been able to assess the effects of elevated transporter expression using BAC transgenic methods (DAT-tg, VMAT2-HI mice). Complemented with in vitro work and neurochemical techniques to assess dopamine compartmentalization, a new focus on the importance of transporter proteins as both models of human disease and potential drug targets has emerged. Here, we review the importance of DAT and VMAT2 function in the delicate balance of neuronal dopamine.
Topics: Animals; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Humans; Mesencephalon; Presynaptic Terminals; Synaptic Transmission
PubMed: 27520881
DOI: 10.1111/ejn.13357 -
Neurochemical Research Jun 2020Dopamine (DA) is critical for motivation, reward, movement initiation, and learning. Mechanisms that control DA signaling have a profound impact on these important... (Review)
Review
Dopamine (DA) is critical for motivation, reward, movement initiation, and learning. Mechanisms that control DA signaling have a profound impact on these important behaviors, and additionally play a role in DA-related neuropathologies. The presynaptic SLC6 DA transporter (DAT) limits extracellular DA levels by clearing released DA, and is potently inhibited by addictive and therapeutic psychostimulants. Decades of evidence support that the DAT is subject to acute regulation by a number of signaling pathways, and that endocytic trafficking strongly regulates DAT availability and function. DAT trafficking studies have been performed in a variety of model systems, including both in vitro and ex vivo preparations. In this review, we focus on the breadth of DAT trafficking studies, with specific attention to, and comparison of, how context may influence DAT's response to different stimuli. In particular, this overview highlights that stimulated DAT trafficking not only differs between in vitro and ex vivo environments, but also is influenced by both sex and anatomical subregions.
Topics: Animals; Brain; Dopamine; Dopamine Plasma Membrane Transport Proteins; GABA Plasma Membrane Transport Proteins; Humans; Protein Transport; Signal Transduction
PubMed: 32146647
DOI: 10.1007/s11064-020-03001-6 -
Brain Research Bulletin Apr 2020Parkinson's disease (PD) is a neurodegenerative disorder accompanied by depletion of dopamine(DA) and loss of dopaminergic (DAergic) neurons in the brain that is... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder accompanied by depletion of dopamine(DA) and loss of dopaminergic (DAergic) neurons in the brain that is believed to be responsible for the motor and non-motor symptoms of PD. Dopamine Transporter (DAT) is essential for reuptake of DA into the presynaptic terminal, thereby controlling the availability and spatial activity of released DA. Parkin interacts with proteins involved in the endosomal pathway, suggesting that presynaptic Parkin could regulate the expression of DAT in the plasma membrane. Parkin mutations lead to early synaptic damage and it appears as a crucial gene having a vast functioning area. PD-specific induced pluripotent stem cells (iPSCs) derived DA neurons exist as a potential tool for in-vitro modeling of PD, as they can recapitulate the pathological features of PD. The exact mechanism of PARKIN influenced DAT variations and changes in DA reuptake by DAT remain unknown. Hence, DAT and PARKIN mutated PD-specific iPSCs-derived DA neurons could provide important clues for elucidating the pathogenesis and mechanism of PD. This mysterious and hidden connection may prove to be a boon in disguise, hence, here we review the influence of PARKIN and DAT on DA mechanism and will discuss how these findings underpin the concept of how downregulation or upregulation of DAT is influenced by PARKIN. We conclude that the establishment of new model for PD with a combination of DAT and PARKIN would have a high translational potential, which includes the identification of drug targets and testing of known and novel therapeutic agents.
Topics: Animals; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Humans; Parkinson Disease; Synapses; Ubiquitin-Protein Ligases
PubMed: 32035946
DOI: 10.1016/j.brainresbull.2020.02.001 -
Parkinsonism & Related Disorders Oct 2020Idiopathic Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterised by the progressive loss of dopaminergic nigrostriatal terminals.... (Review)
Review
Idiopathic Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterised by the progressive loss of dopaminergic nigrostriatal terminals. Currently, in early idiopathic PD, dopamine transporter (DAT)-specific imaging assesses the extent of striatal dopaminergic deficits, and conventional magnetic resonance imaging (MRI) of the brain excludes the presence of significant ischaemic load in the basal ganglia as well as signs indicative of other forms of Parkinsonism. In this article, we discuss the use of multimodal DAT-specific and MRI protocols for insight into the early pathological features of idiopathic PD, including: structural MRI, diffusion tensor imaging, nigrosomal iron imaging and neuromelanin-sensitive MRI sequences. These measures may be acquired serially or simultaneously in a hybrid scanner. From current evidence, it appears that both nigrosomal iron imaging and neuromelanin-sensitive MRI combined with DAT-specific imaging are useful to assist clinicians in diagnosing PD, while conventional structural MRI and diffusion tensor imaging protocols are better suited to a research context focused on characterising early PD pathology. We believe that in the future multimodal imaging will be able to characterise prodromal PD and stratify the clinical stages of PD progression.
Topics: Dopamine Plasma Membrane Transport Proteins; Magnetic Resonance Imaging; Multimodal Imaging; Neuroimaging; Parkinson Disease
PubMed: 32861103
DOI: 10.1016/j.parkreldis.2020.08.010