Regulation of dopamine transporter function by protein-protein interactions: new discoveries and methodological challenges

TY - JOUR

T1 - Regulation of dopamine transporter function by protein-protein interactions: new discoveries and methodological challenges

AU - Eriksen, Jacob

AU - Jørgensen, Trine Nygaard

AU - Gether, Ulrik

N1 - Keywords: Animals; Brain; Dopamine; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Electric Conductivity; Fluorescent Antibody Technique; Fluorescent Dyes; Ion Transport; Models, Biological; Neurons; Protein Conformation; Protein Processing, Post-Translational; Protein Transport; Receptors, G-Protein-Coupled; Ubiquitination; alpha-Synuclein

PY - 2010/4

Y1 - 2010/4

N2 - The dopamine transporter (DAT) plays a key role in regulating dopaminergic signalling in the brain by mediating rapid clearance of dopamine from the synaptic clefts. The psychostimulatory actions of cocaine and amphetamine are primarily the result of a direct interaction of these compounds with DAT leading to attenuated dopamine clearance and for amphetamine even increased dopamine release. In the last decade, intensive efforts have been directed towards understanding the molecular and cellular mechanisms governing the activity and availability of DAT in the plasma membrane of the pre-synaptic neurons. This has led to the identification of a plethora of different kinases, receptors and scaffolding proteins that interact with DAT and hereby either modulate the catalytic activity of the transporter or regulate its trafficking and degradation. Several new tools for studying DAT regulation in live cells have also recently become available such as fluorescently tagged cocaine analogues and fluorescent substrates. Here we review the current knowledge about the role of protein-protein interactions in DAT regulation as well as we describe the most recent methodological developments that have been established to overcome the challenges associated with the study of DAT in endogenous systems.

AB - The dopamine transporter (DAT) plays a key role in regulating dopaminergic signalling in the brain by mediating rapid clearance of dopamine from the synaptic clefts. The psychostimulatory actions of cocaine and amphetamine are primarily the result of a direct interaction of these compounds with DAT leading to attenuated dopamine clearance and for amphetamine even increased dopamine release. In the last decade, intensive efforts have been directed towards understanding the molecular and cellular mechanisms governing the activity and availability of DAT in the plasma membrane of the pre-synaptic neurons. This has led to the identification of a plethora of different kinases, receptors and scaffolding proteins that interact with DAT and hereby either modulate the catalytic activity of the transporter or regulate its trafficking and degradation. Several new tools for studying DAT regulation in live cells have also recently become available such as fluorescently tagged cocaine analogues and fluorescent substrates. Here we review the current knowledge about the role of protein-protein interactions in DAT regulation as well as we describe the most recent methodological developments that have been established to overcome the challenges associated with the study of DAT in endogenous systems.

U2 - 10.1111/j.1471-4159.2010.06599.x

DO - 10.1111/j.1471-4159.2010.06599.x

M3 - Journal article

C2 - 20085610

SN - 0022-3042

VL - 113

SP - 27

EP - 41

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

IS - 1

ER -