Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1.
PDZ domain-containing proteins play an important role in the targeting and localization of synaptic membrane proteins. Here, we report an interaction between the PDZ domain-containing protein PICK1 and monoamine neurotransmitter transporters in vitro and in vivo. In dopaminergic neurons, PICK1 colocalizes with the dopamine transporter (DAT) and forms a stable protein complex. Coexpression of PICK1 with DAT in mammalian cells and neurons in culture results in colocalization of the two proteins in a cluster pattern and an enhancement of DAT uptake activity through an increase in the number of plasma membrane DAT. Deletion of the PDZ binding site at the carboxyl terminus of DAT abolishes its association with PICK1 and impairs the localization of the transporter in neurons. These findings indicate a role for PDZ-mediated protein interactions in the localization, expression, and function of monoamine transporters.
Torres
G E
GE
Howard Hughes Medical Institute, Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Yao
W D
WD
Mohn
A R
AR
Quan
H
H
Kim
K M
KM
Levey
A I
AI
Staudinger
J
J
Caron
M G
MG
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005333:Fetus; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009687:Nuclear Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D027981:Symporters; D013570:Synaptic Membranes / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D015003:Yeasts / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009687:Nuclear Proteins; C091822:Prkcabp protein, mouse; C493228:Slc6a2 protein, mouse; C493215:Slc6a3 protein, mouse; D027981:Symporters; D020794:Receptor Protein-Tyrosine Kinases; D004298:Dopamine