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Regulation of dopamine transporter function by the PDZ domain protein PICK1
Project Acronym:PICK1 AND DAT
|Organization name:KOBENHAVNS UNIVERSITET|
Objective: The dopamine transporter (DAT) belongs to the family of Na+/Cl- dependent neurotransmitter transporters and is responsible for rapid termination of dopaminergic signalling 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.
Project cost:201923 EURO
Project Funding:201923 EURO
Programme Acronym: FP7-PEOPLE
Programme type:Seventh Framework Programme
Subprogramme Area:Marie Curie Action: "Intra-European Fellowships for Career Development"
Contract type:Intra-European Fellowships (IEF)
Subject index:Education, Training, Scientific Research
Other Indexes:drug addiction,Neurobiology,schizophrenia,PKC,Degenerative diseases,dopamine transporter,PICK1,amphetamine
Record control number:88727