Objective The dopamine transporter (DAT) belongs to the family of Na+/Cl- dependent neurotransmitter transporters and is responsible for rapid termination of dopaminergic signaling by mediating reuptake of dopamine (DA) from the synaptic cleft. The DAT is target for widely abused psychostimulants, such as amphetamine and cocaine, as well as modification in DAT activity has been associated with severe brain disorders like Parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder (ADHD). An increasing number of proteins have been identified as interaction partners of the DAT but the functional implications of the interactions are poorly understood. Here we propose to investigate the molecular significance of the interaction between DAT and the PDZ domain protein PICK1. Based on a series of preliminary data we propose that binding of PICK1 via its PDZ domain to the DAT C-terminus operate to regulate uncoupled DAT mediated currents. Notably, these currents are likely to modulate the excitability of dopaminergic neurons and thereby the overall activity of the dopamine system. We hypothesize that PICK1 mediated regulation of these currents either involves enhanced DAT phosphorylation due to PICK1 mediated recruitment of protein kinase Ca or modulation of intramolecular interactions in the transporter molecule. We will test our hypotheses by employing an interdisciplinary strategy that combines the expertise of the applicants with those of the host laboratory and involves a broad spectrum of methods including patch clamp measurements, bioimaging and molecular biological procedures. We expect that the project will lead to significant improvement of our understanding of DAT regulation and thereby provide an important framework for future discovery of novel therapeutic strategies against diseases characterized by dopaminergic dysfunction. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineneurologyparkinsonmedical and health sciencesclinical medicinepsychiatryschizophrenia Keywords Degenerative diseases Neurobiology PICK1 PKC amphetamine dopamine transporter drug addiction schizophrenia Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) PEOPLE-2007-2-1.IEF - Marie Curie Action: "Intra-European Fellowships for Career Development" Call for proposal FP7-PEOPLE-2007-2-1-IEF See other projects for this call Funding Scheme MC-IEF - Intra-European Fellowships (IEF) Coordinator KOBENHAVNS UNIVERSITET EU contribution € 201 923,71 Address NORREGADE 10 1165 Kobenhavn Denmark See on map Region Danmark Hovedstaden Byen København Activity type Higher or Secondary Education Establishments Administrative Contact Ulrik Gether (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
