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

Mattias Rickhag, Freja Herborg Hansen, Gunnar Sørensen, Kristine Nørgaard Strandfelt, Bjørn Andresen, Kamil Gotfryd, Kenneth L. Madsen, Ib Vestergaard Klewe, Ina Ammendrup-Johnsen, Jacob Eriksen, Amy H. Newman, Ernst-Martin Füchtbauer, Jesus Gomeza, David P.D. Woldbye, Gitta Wörtwein and Ulrik Gether ()
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Mattias Rickhag: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Freja Herborg Hansen: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Gunnar Sørensen: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Kristine Nørgaard Strandfelt: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Bjørn Andresen: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Kamil Gotfryd: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Kenneth L. Madsen: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Ib Vestergaard Klewe: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Ina Ammendrup-Johnsen: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Jacob Eriksen: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen
Amy H. Newman: National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health
Ernst-Martin Füchtbauer: Aarhus University
Jesus Gomeza: Institute for Pharmaceutical Biology, University of Bonn
David P.D. Woldbye: Laboratory of Neuropsychiatry, Faculty of Health and Medical Sciences, University of Copenhagen
Gitta Wörtwein: Laboratory of Neuropsychiatry, Faculty of Health and Medical Sciences, University of Copenhagen
Ulrik Gether: Molecular Neuropharmacology Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Faculty of Health and Medical Sciences, University of Copenhagen

Nature Communications, 2013, vol. 4, issue 1, 1-14

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms2568

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