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

Karl 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, Ulrik Gether

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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.
Original languageEnglish
Article number1580
JournalNature Communications
Volume4
Pages (from-to)1-13
Number of pages13
ISSN2041-1723
DOIs
Publication statusPublished - 2013

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