Article
- The EMBO Journal (2007) 26, 2127 - 2136
- doi:10.1038/sj.emboj.7601656
Published online: 22 March 2007
Subject Category:
Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor
Frank JS Lee1,a, Lin Pei1,a, Anna Moszczynska1,a, Brian Vukusic1, Paul J Fletcher1,2,3 and Fang Liu1,2,4,5
- Department of Neuroscience, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
- Department of Psychology, University of Toronto, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
Correspondence to:
Fang Liu, Department of Neuroscience, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8. Tel.: +1 416 979 4659; Fax: +1 416 979 4663; E-mail: fang_liu@camh.net
aThese authors contributed equally to this work
Received 10 May 2006; Accepted 27 February 2007
Abstract
Altered synaptic dopamine levels have been implicated in several neurological/neuropsychiatric disorders, including drug addiction and schizophrenia. However, it is unclear what precipitates these changes in synaptic dopamine levels. One of the key presynaptic components involved in regulating dopaminergic tone is the dopamine transporter (DAT). Here, we report that the DAT is also regulated by the dopamine D2 receptor through a direct protein–protein interaction involving the DAT amino-terminus and the third intracellular loop of the D2 receptor. This physical coupling facilitates the recruitment of intracellular DAT to the plasma membrane and leads to enhanced dopamine reuptake. Moreover, mice injected with peptides that disrupt D2–DAT interaction exhibit decreased synaptosomal dopamine uptake and significantly increased locomotor activity, reminiscent of DAT knockout mice. Our data highlight a novel mechanism through which neurotransmitter receptors can functionally modulate neurotransmitter transporters, an interaction that can affect the synaptic neurotransmitter levels in the brain.
Keywords:
- autoreceptor,
- catecholamine,
- dopamine,
- transport,
- uptake
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