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    The Dopamine Transporter Recycles via a Retromer-Dependent Postendocytic Mechanism: Tracking Studies Using a Novel Fluorophore-Coupling Approach

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    Authors
    Wu, Sijia
    Fagan, Rita R.
    Uttamapinant, Chayasith
    Lifshitz, Lawrence M.
    Fogarty, Kevin E.
    Ting, Alice Y.
    Melikian, Haley E.
    Student Authors
    Sijia Wu
    Rita Fagan
    Academic Program
    Neuroscience
    UMass Chan Affiliations
    Graduate School of Biomedical Sciences, Program in Neuroscience
    Melikian Lab
    Biomedical Imaging Group, Program in Molecular Medicine
    Department of Psychiatry
    Brudnick Neuropsychiatric Research Institute
    Document Type
    Journal Article
    Publication Date
    2017-09-27
    Keywords
    cocaine
    dopamine
    endocytosis
    retromer
    reuptake
    trafficking
    Heterocyclic Compounds
    Molecular and Cellular Neuroscience
    Nervous System
    Organic Chemicals
    
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    Abstract
    Presynaptic reuptake, mediated by the dopamine (DA) transporter (DAT), terminates DAergic neurotransmission and constrains extracellular DA levels. Addictive and therapeutic psychostimulants inhibit DA reuptake and multiple DAT coding variants have been reported in patients with neuropsychiatric disorders. These findings underscore that DAT is critical for DA neurotransmission and homeostasis. DAT surface availability is regulated acutely by endocytic trafficking, and considerable effort has been directed toward understanding mechanisms that govern DAT's plasma membrane expression and postendocytic fate. Multiple studies have demonstrated DAT endocytic recycling and enhanced surface delivery in response to various stimuli. Paradoxically, imaging studies have not detected DAT targeting to classic recycling endosomes, suggesting that internalized DAT targets to either degradation or an undefined recycling compartment. Here, we leveraged PRIME (PRobe Incorporation Mediated by Enzyme) labeling to couple surface DAT directly to fluorophore, and tracked DAT's postendocytic itinerary in immortalized mesencephalic cells. Following internalization, DAT robustly targeted to retromer-positive endosomes, and DAT/retromer colocalization was observed in male mouse dopaminergic somatodendritic and terminal regions. Short hairpin RNA-mediated Vps35 knockdown revealed that DAT endocytic recycling requires intact retromer. DAT also targeted rab7-positive endosomes with slow, linear kinetics that were unaffected by either accelerating DAT internalization or binding a high-affinity cocaine analog. However, cocaine increased DAT exit from retromer-positive endosomes significantly. Finally, we found that the DAT carboxy-terminal PDZ-binding motif was required for DAT recycling and exit from retromer. These results define the DAT recycling mechanism and provide a unifying explanation for previous, seemingly disparate, DAT endocytic trafficking findings. SIGNIFICANCE STATEMENT The neuronal dopamine (DA) transporter (DAT) recaptures released DA and modulates DAergic neurotransmission, and a number of DAT coding variants have been reported in several DA-related disorders, including infantile parkinsonism, attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is also competitively inhibited by psychostimulants with high abuse potential. Therefore, mechanisms that acutely affect DAT availability will likely exert significant impact on both normal and pathological DAergic homeostasis. Here, we explore the cellular mechanisms that acutely control DAT surface expression. Our results reveal the intracellular mechanisms that mediate DAT endocytic recycling following constitutive and regulated internalization. In addition to shedding light on this critical process, these findings resolve conflict among multiple, seemingly disparate, previous reports on DAT's postendocytic fate.
    Source

    J Neurosci. 2017 Sep 27;37(39):9438-9452. doi: 10.1523/JNEUROSCI.3885-16.2017. Epub 2017 Aug 28. Link to article on publisher's site

    DOI
    10.1523/JNEUROSCI.3885-16.2017
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/29229
    PubMed ID
    28847807
    Related Resources

    Link to Article in PubMed

    Rights
    Copyright © 2017 the authors. Publisher PDF posted after 6 months as allowed by the publisher's author rights policy at http://www.jneurosci.org/sites/default/files/files/JN_License_to_Publish.pdf.
    ae974a485f413a2113503eed53cd6c53
    10.1523/JNEUROSCI.3885-16.2017
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    Morningside GSBS Scholarly Publications
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