Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/ncomms2568
Keywords
-
Categories
Funding
- 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
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available