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A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter

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  • Karl Mattias Rickhag, Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Freja Herborg Hansen, Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen
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  • Gunnar Sørensen, Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen
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  • Kristine Nørgaard Strandfelt, Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Bjørn Andresen, Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen
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  • Kamil Gotfryd, Denmark
  • Kenneth L Madsen, Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and
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  • Ib Vestergaard Klewe, Neuropharm and Genetics Lab, Denmark
  • Ina Ammendrup-Johnsen, Institut for Neurovidenskab og Farmakologi, Denmark
  • Jacob Eriksen, Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen
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  • Amy H Newman, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health
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  • Ernst-Martin Füchtbauer
  • Jesus Gomeza, Institute for Pharmaceutical Biology, University of Bonn
  • ,
  • David P D Woldbye, Denmark
  • Gitta Wörtwein, Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • Ulrik Gether, Denmark
The dopamine transporter mediates reuptake of dopamine from the synaptic cleft. The cellular mechanisms controlling dopamine transporter levels in striatal nerve terminals remain poorly understood. The dopamine transporters contain a C-terminal PDZ (PSD-95/Discs-large/ZO-1) domain-binding sequence believed to bind synaptic scaffolding proteins, but its functional significance is uncertain. Here we demonstrate that two different dopamine transporter knock-in mice with disrupted PDZ-binding motifs (dopamine transporter-AAA and dopamine transporter+Ala) are characterized by dramatic loss of dopamine transporter expression in the striatum, causing hyperlocomotion and attenuated response to amphetamine. In cultured dopaminergic neurons and striatal slices from dopamine transporter-AAA mice, we find markedly reduced dopamine transporter surface levels and evidence for enhanced constitutive internalization. In dopamine transporter-AAA neurons, but not in wild-type neurons, surface levels are rescued in part by expression of a dominant-negative dynamin mutation (K44A). Our findings suggest that PDZ-domain interactions are critical for synaptic distribution of dopamine transporter in vivo and thereby for proper maintenance of dopamine homoeostasis.
Original languageEnglish
Article number1580
JournalNature Communications
Volume4
Number of pages14
ISSN2041-1723
DOIs
Publication statusPublished - 12 Mar 2013

    Research areas

  • Amino Acid Sequence, Amphetamine, Animals, Behavior, Animal, Binding Sites, Biological Transport, Carrier Proteins, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopaminergic Neurons, Endocytosis, Endoplasmic Reticulum, Immunohistochemistry, Locomotion, Mice, Mice, Knockout, Mutation, Neostriatum, Nuclear Proteins, PDZ Domains, Phenotype, Presynaptic Terminals, Protein Binding, Structure-Activity Relationship

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