期刊
NATURE COMMUNICATIONS
卷 4, 期 -, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/ncomms2568
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资金
- National Institute of Health [P01 DA 12408]
- Danish Medical Research Council
- University of Copenhagen BioScaRT Program of Excellence
- Lundbeck Foundation Center for Biomembranes in Nanomedicine
- Lundbeck Foundation
- Novo Nordisk Foundation
- Fabrikant Vilhelm Pedersen og Hustrus Mindelegat
- Lundbeck Foundation [R77-2010-6815] Funding Source: researchfish
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 wildtype 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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