The dopamine (DA) transporter (DAT) is critical in the re-uptake of DA into presynaptic neurons and the termination of dopamine signaling. Alterations in DA signaling is evident in several disease pathologies including ADHD, Parkinson's disease and schizophrenia. Recently, it has been shown that intracellular proteins interact with and affect the localization and function of DAT. As such, we hypothesize that DAT exists in a protein complex that regulates the activity of the transporter. To test this hypothesis we will take advantage of the model system C. elegans to test candidate regulatory proteins for DAT and identify novel proteins that associate with the transporter. The C. elegans dopamine transporter DAT-1) shows a 45% homology to the human transporter, with a sensitivity to amphetamines, cocaine, and other biogenic amine transporter antagonists. In my proposal, I build on recent studies by our laboratory on DAT-1 to: 1) determine the expression level and localization of DAT-1, 2) characterize the interactions of the C. elegans PICK1 homologue (Y57G11C.22) with DAT-1 and, 3) identify novel proteins that interact with the C. elegans dopamine transporter. These studies will increase our understanding of intrinsic modulatory influences controlling DA signaling in vivo and in disease states.
| McDonald, Paul W; Hardie, Shannon L; Jessen, Tammy N et al. (2007) Vigorous motor activity in Caenorhabditis elegans requires efficient clearance of dopamine mediated by synaptic localization of the dopamine transporter DAT-1. J Neurosci 27:14216-27 |
| Nass, Richard; Hahn, Maureen K; Jessen, Tammy et al. (2005) A genetic screen in Caenorhabditis elegans for dopamine neuron insensitivity to 6-hydroxydopamine identifies dopamine transporter mutants impacting transporter biosynthesis and trafficking. J Neurochem 94:774-85 |
