| First Author | Rickhag M | Year | 2013 |
| Journal | Nat Commun | Volume | 4 |
| Pages | 1580 | PubMed ID | 23481388 |
| Mgi Jnum | J:266803 | Mgi Id | MGI:6213980 |
| Doi | 10.1038/ncomms2568 | Citation | Rickhag M, et al. (2013) A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter. Nat Commun 4:1580 |
| abstractText | 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. |
