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

doi:10.1038/ncomms2568

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

31 Citations (Scopus)

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 language	English
Article number	1580
Journal	Nature Communications
Volume	4
Pages (from-to)	1-13
Number of pages	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms2568
Publication status	Published - 2013

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Rickhag, K. M., Hansen, F. H., Sørensen, G., Strandfelt, K. N., Andresen, B., Gotfryd, K., Madsen, K. L., Vestergaard-Klewe, I., Ammendrup-Johnsen, I., Eriksen, J., Newman, A. H., Füchtbauer, E-M., Gomeza, J., Woldbye, D. P. D., Wörtwein, G., & Gether, U. (2013). A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter. Nature Communications, 4, 1-13. [1580]. https://doi.org/10.1038/ncomms2568

Rickhag, KM , Hansen, FH, Sørensen, G, Strandfelt, KN, Andresen, B, Gotfryd, K, Madsen, KL, Vestergaard-Klewe, I, Ammendrup-Johnsen, I, Eriksen, J, Newman, AH, Füchtbauer, E-M, Gomeza, J, Woldbye, DPD , Wörtwein, G & Gether, U 2013, 'A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter', Nature Communications, vol. 4, 1580, pp. 1-13. https://doi.org/10.1038/ncomms2568

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

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.",

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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

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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.

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DO - 10.1038/ncomms2568

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C2 - 23481388

SN - 2041-1723

VL - 4

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

M1 - 1580

ER -

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

Abstract

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