TY - JOUR
T1 - A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter
AU - Rickhag, Karl Mattias
AU - Hansen, Freja Herborg
AU - Sørensen, Gunnar
AU - Strandfelt, Kristine Nørgaard
AU - Andresen, Bjørn
AU - Gotfryd, Kamil
AU - Madsen, Kenneth L
AU - Vestergaard-Klewe, Ib
AU - Ammendrup-Johnsen, Ina
AU - Eriksen, Jacob
AU - Newman, Amy H
AU - Füchtbauer, Ernst-Martin
AU - Gomeza, Jesus
AU - Woldbye, David P D
AU - Wörtwein, Gitta
AU - Gether, Ulrik
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms2568
DO - 10.1038/ncomms2568
M3 - Journal article
C2 - 23481388
VL - 4
SP - 1
EP - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 1580
ER -