Mechanisms of dopamine transporter regulation in normal and disease states
TL;DR: The transport and binding properties of DAT are regulated by complex and overlapping mechanisms that provide neurons with the ability to modulate DA clearance in response to physiological demands, demonstrating their importance for normal neurotransmission, drug abuse, and disease treatments.
About: This article is published in Trends in Pharmacological Sciences.The article was published on 2013-09-01 and is currently open access. It has received 338 citations till now. The article focuses on the topics: Dopamine transporter & Dopaminergic.
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TL;DR: A vicious cycle of accumulating α-Syn and deregulated dopamine that triggers synaptic dysfunction and impaired neuronal communication, ultimately causing synaptopathy and progressive neurodegeneration in Parkinson's disease is suggested.
Abstract: Parkinson's disease (PD) is characterized by intracellular inclusions of aggregated and misfolded α-Synuclein (α-Syn), and the loss of dopaminergic (DA) neurons in the brain. The resulting motor abnormalities mark the progression of PD, while non-motor symptoms can already be identified during early, prodromal stages of disease. Recent studies provide evidence that during this early prodromal phase, synaptic and axonal abnormalities occur before the degenerative loss of neuronal cell bodies. These early phenotypes can be attributed to synaptic accumulation of toxic α-Syn. Under physiological conditions, α-Syn functions in its native conformation as a soluble monomer. However, PD patient brains are characterized by intracellular inclusions of insoluble fibrils. Yet, oligomers and protofibrils of α-Syn have been identified to be the most toxic species, with their accumulation at presynaptic terminals affecting several steps of neurotransmitter release. First, high levels of α-Syn alter the size of synaptic vesicle pools and impair their trafficking. Second, α-Syn overexpression can either misregulate or redistribute proteins of the presynaptic SNARE complex. This leads to deficient tethering, docking, priming and fusion of synaptic vesicles at the active zone (AZ). Third, α-Syn inclusions are found within the presynaptic AZ, accompanied by a decrease in AZ protein levels. Furthermore, α-Syn overexpression reduces the endocytic retrieval of synaptic vesicle membranes during vesicle recycling. These presynaptic alterations mediated by accumulation of α-Syn, together impair neurotransmitter exocytosis and neuronal communication. Although α-Syn is expressed throughout the brain and enriched at presynaptic terminals, DA neurons are the most vulnerable in PD, likely because α-Syn directly regulates dopamine levels. Indeed, evidence suggests that α-Syn is a negative modulator of dopamine by inhibiting enzymes responsible for its synthesis. In addition, α-Syn is able to interact with and reduce the activity of VMAT2 and DAT. The resulting dysregulation of dopamine levels directly contributes to the formation of toxic α-Syn oligomers. Together these data suggest a vicious cycle of accumulating α-Syn and deregulated dopamine that triggers synaptic dysfunction and impaired neuronal communication, ultimately causing synaptopathy and progressive neurodegeneration in Parkinson's disease.
234 citations
Cites background from "Mechanisms of dopamine transporter ..."
...DAT transports dopamine from the synaptic cleft back into the cytoplasm is the primary mechanism and possibly the most important regulator of extracellular dopamine concentrations (Vaughan and Foster, 2013)....
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TL;DR: An oestrous cycle-dependent mechanism controlling increased cocaine reward in females is demonstrated and a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing is defined.
Abstract: Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing.
228 citations
TL;DR: A credible transport model must account for monoaminergic neurons' distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects.
217 citations
Cites background or methods from "Mechanisms of dopamine transporter ..."
...The figure was obtained and modified with permission from James Foster and Roxanne Vaughan [64]....
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...The kinases involved include protein kinase B (Akt), protein kinase C (PKC), protein kinase G (PKG), extracellular signal regulated kinase (ERK), casein kinase II (CKII), Ca2+/calmodulin-dependent protein kinase IIα (αCaMKII), p38 MAP Kinase (MAPK; see selected overview in Figure I and [64,91] for comprehensive review,)....
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...Fourth, there is ample evidence that the phosphorylation in DAT and also SERT contribute to the action of amphetamines (reviewed in [64]): amphetamine-induced efflux is blunted by elimination of the phosphorylation sites in the N-terminus of DAT [41] or by inhibition of either PKC or αCaMKII [50,65–69]....
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..., phosphorylation, ubiquitylation, and palmitoylation – as indicated in Figure I and [21,64])....
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TL;DR: The anatomical and functional connections allowing the LHb to control the dopamine and serotonin systems are described, as well as possible roles of these connections in motivated behaviors and neuropsychiatric disorders.
Abstract: The lateral habenula (LHb) is an epithalamic region with a crucial role in the regulation of midbrain monoaminergic systems. Over the past few years a renewed interest in the LHb has emerged due to studies highlighting its central role in encoding rewarding and aversive aspects of stimuli. Moreover, an increasing number of functional as well as behavioral indications provide substantial evidence supporting a role of LHb in neuropsychiatric diseases, including mood disorders and drug addiction. Cellular and synaptic adaptations in the LHb may therefore represent a critical phenomenon in the etiology of these diseases. In the current review we describe the anatomical and functional connections allowing the LHb to control the dopamine and serotonin systems, as well as possible roles of these connections in motivated behaviors and neuropsychiatric disorders. Finally, we discuss how drug exposure and stressful conditions alter the cellular physiology of the LHb, highlighting a role for the LHb in the context of drug addiction and depression.
160 citations
Cites background from "Mechanisms of dopamine transporter ..."
...A prominent mechanism of action of both these drugs is that they strongly enhance DA levels by acting on the DA transporter (DAT; Vaughan & Foster, 2013)....
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TL;DR: This review provides an overview of the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects and how selected drugs alter the function and expression of these transporters.
Abstract: Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson’s disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein–protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders.
149 citations
Cites background from "Mechanisms of dopamine transporter ..."
...These are not all encompassing, and the reader is referred to additional recent reviews (Sulzer et al., 2005; Alter et al., 2013; Schmitt et al., 2013; Vaughan and Foster, 2013; Howell and Negus, 2014; Nickell et al., 2014)....
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References
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TL;DR: The structure of a bacterial homologue of these transporters from Aquifex aeolicus, in complex with its substrate, leucine, and two sodium ions, is presented and reveals the architecture of this important class of transporter, illuminates the determinants of substrate binding and ion selectivity, and defines the external and internal gates.
Abstract: The present invention relates to three dimensional structural models of the LeuTAa transporter, and, in particular, the modeled sites of these proteins. The structural information of the present invention may be used for the rational design of compounds which act as modulators of the LeuTAa transporter and its eukaryotic counterparts. The present invention further provides for actual or virtual screening assays which may be used to identify compounds having such modulator activities, or to confirm the activity of designed compounds.
1,518 citations
"Mechanisms of dopamine transporter ..." refers background in this paper
...Regulatory elements of rat dopamine transporter N- and C-terminal domains A 3D model of rat DAT based on the A. aeolicus LeuT transporter was generated using PyMol (Schrödinger, LLC), with TM helices shown as barrels and light shading indicating semitransparent Connolly surfaces....
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...Great insights on the core structure have been obtained from homology modeling to the bacterial leucine transporter LeuT [1, 10], but far less is known about the cytoplasmic domains, which are not conserved in LeuT and whose structures have not been solved....
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...Krishnamurthy H, Gouaux E. X-ray structures of LeuT in substrate-free outward-open and apo inward-open states....
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...Beuming T, et al. A comprehensive structure-based alignment of prokaryotic and eukaryotic neurotransmitter/Na+ symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function....
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TL;DR: A consensus definition of a membrane raft is emerged that helps to clarify current thinking in a field that has been plagued by the heterogeneous and sometimes ephemeral nature of its subject.
1,427 citations
"Mechanisms of dopamine transporter ..." refers background in this paper
...Membrane rafts are cholesterol- and sphingolipid-rich microdomains that are specialized for particular cellular functions such as receptor signaling via segregation of specific protein populations [61]....
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TL;DR: Questions about the molecular actions of addictive drugs, prominently including the actions of alcohol and solvents, remain unresolved, but their ability to co-opt normal presynaptic functions helps to explain why treatment for addiction has been challenging.
529 citations
"Mechanisms of dopamine transporter ..." refers background in this paper
...AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]....
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TL;DR: Crystal structures of LeuT mutants in complexes with conformation-specific antibody fragments in the outward-open and inward-open states establish a structural framework for the mechanism of neurotransmitter sodium symporters and their modulation by therapeutic and illicit substances.
Abstract: Neurotransmitter sodium symporters are integral membrane proteins that remove chemical transmitters from the synapse and terminate neurotransmission mediated by serotonin, dopamine, noradrenaline, glycine and GABA (γ-aminobutyric acid). Crystal structures of the bacterial homologue, LeuT, in substrate-bound outward-occluded and competitive inhibitor-bound outward-facing states have advanced our mechanistic understanding of neurotransmitter sodium symporters but have left fundamental questions unanswered. Here we report crystal structures of LeuT mutants in complexes with conformation-specific antibody fragments in the outward-open and inward-open states. In the absence of substrate but in the presence of sodium the transporter is outward-open, illustrating how the binding of substrate closes the extracellular gate through local conformational changes: hinge-bending movements of the extracellular halves of transmembrane domains 1, 2 and 6, together with translation of extracellular loop 4. The inward-open conformation, by contrast, involves large-scale conformational changes, including a reorientation of transmembrane domains 1, 2, 5, 6 and 7, a marked hinge bending of transmembrane domain 1a and occlusion of the extracellular vestibule by extracellular loop 4. These changes close the extracellular gate, open an intracellular vestibule, and largely disrupt the two sodium sites, thus providing a mechanism by which ions and substrate are released to the cytoplasm. The new structures establish a structural framework for the mechanism of neurotransmitter sodium symporters and their modulation by therapeutic and illicit substances.
481 citations
"Mechanisms of dopamine transporter ..." refers background in this paper
...V382A DAT displays decreased DA affinity, increased cocaine affinity, and altered PKC-dependent regulation [91, 92], while V55A displays increased DA Km and decreased cocaine affinity [48, 92]....
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TL;DR: It is reported that α-synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non-Aβ amyloid component of α- synuclein to the carboxyl-terminal tail of the hDAT accelerate dopamine-induced apoptosis.
Abstract: Mutations in α-synuclein, a protein highly enriched in presynaptic terminals, have been implicated in the expression of familial forms of Parkinson’s disease (PD) whereas native α-synuclein is a major component of intraneuronal inclusion bodies characteristic of PD and other neurodegenerative disorders. Although overexpression of human α-synuclein induces dopaminergic nerve terminal degeneration, the molecular mechanism by which α-synuclein contributes to the degeneration of these pathways remains enigmatic. We report here that α-synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non-Aβ amyloid component of α-synuclein to the carboxyl-terminal tail of the hDAT. α-Synuclein–hDAT complex formation facilitates the membrane clustering of the DAT, thereby accelerating cellular dopamine uptake and dopamine-induced cellular apoptosis. Since the selective vulnerability of dopaminergic neurons in PD has been ascribed ...
457 citations