A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter
Research output: Contribution to journal › Journal article › Research › peer-review
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 language | English |
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Article number | 1580 |
Journal | Nature Communications |
Volume | 4 |
Pages (from-to) | 1-13 |
Number of pages | 13 |
ISSN | 2041-1723 |
DOIs | |
Publication status | Published - 2013 |
ID: 45487632