Re-uptake of neurotransmitters from the synaptic cleft is considered to a critical component in the termination of synaptic transmission. The dopamine transporter (DAT) plays a fundamental role (DAT) plays a fundamental role in maintaining the extracellular levels of dopamine thereby controlling the duration and the intensity of dopaminergic transmission. It is also a target site of anti-depressants and psychostimulants such as cocaine and amphetamine. Despite the importance of this molecule in the pathophysiology of affective disorders and drug abuse, little is known about the basic regulatory components associated with the molecular and cellular biology of this membrane protein. The studied proposed in this application are designed to identify novel intracellular proteins that interact with DAT and participate in transporter cellular regulatory mechanisms. In addition, the functional molecular determinants required for the assembly, regulated trafficking, and localization of DAT proteins will also be elucidate. Thus, the goals of this proposal is to delineate functional domains in the DAT protein, relative those domains to cellular regulatory mechanisms, and identify novel components that participate in the regulation of DAT expression and function. This information will provide a foundation for more in- depth studies that could lead to new opportunities for the development of therapeutic interventions used in the management of affective disorders and drug abuse.
| Torres, Gonzalo E; Sweeney, Ava L; Beaulieu, Jean-Martin et al. (2004) Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant. Proc Natl Acad Sci U S A 101:15650-5 |
| Torres, Gonzalo E; Carneiro, Ana; Seamans, Katie et al. (2003) Oligomerization and trafficking of the human dopamine transporter. Mutational analysis identifies critical domains important for the functional expression of the transporter. J Biol Chem 278:2731-9 |
| Carneiro, Ana M; Ingram, Susan L; Beaulieu, Jean-Martin et al. (2002) The multiple LIM domain-containing adaptor protein Hic-5 synaptically colocalizes and interacts with the dopamine transporter. J Neurosci 22:7045-54 |
