Attenuation of the Norepinephrine Transporter Activity and Trafficking Via Interactions with Alpha-synuclein.
From: Department of Biochemistry, Molecular and Cell Biology, Georgetown University, Washington, DC 20007, USA.
The European journal of neuroscience
- Publish Date: Dec 2006
- ISSN: 0953-816X
- Volume: 24
- Issue: 11
- Pages: 3141-52
- Medium: Print
- Language: English
- Citation (JAMA): Wersinger Christophe, Jeannotte Alexis, Sidhu Anita, et al. Attenuation of the Norepinephrine Transporter Activity and Trafficking Via Interactions with Alpha-synuclein.. Eur. J. Neurosci. Dec 2006;24:3141-52
Abstract
Alpha-synuclein (alpha-Syn) has been studied in the context of Parkinson’s disease, but its normative role remains elusive. We have shown that alpha-Syn regulates the homeostasis of dopaminergic and serotonergic synapses, through trafficking of the dopamine and serotonin transporter, respectively. In the present study we sought to determine if alpha-Syn could also modulate noradrenergic signaling, by studying its interactions with the norepinephrine transporter (NET). We co-transfected Ltk- cells with increasing amounts of alpha-Syn DNA and a constant amount of NET DNA, and observed a progressive decrease (68%) in [3H]-NE uptake in cells co-transfected with a ratio of 3:1 alpha-Syn:NET DNA. The Kd of transport did not change, but increasing alpha-Syn caused a decrease in the Vmax of the transporter, from 2.27+/-0.14 to 0.89+/-0.15 pmol/min/10(5) cells, with NET expression alone or 4:1 ratio of alpha-Syn:NET transfection, respectively. Decreases in surface biotinylation and [3H]-nisoxetine binding kinetics in intact cells revealed that NET cell surface expression was attenuated in correlation to the amount of alpha-Syn co-transfected into cells. The interaction between NET and alpha-Syn occurred via the NAC domain of alpha-Syn, the region directly responsible for self-aggregation. These findings are the first to show that alpha-Syn has a central role in the homeostasis of noradrenergic neurons. Together with our previous studies on dopamine and serotonin transporters, we propose that a primary physiological role of alpha-Syn may be to regulate the homeostasis of monoamines in synapses, through modulatory interactions of the protein with monoaminergic transporters.
Mesh Headings (Keywords): Animals, Brain, Cell Line, Homeostasis, Humans, Male, Neurons, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Protein Structure, Tertiary, Protein Transport, Rats, Rats, Sprague-Dawley, Sympathetic Nervous System, Synapses, Synaptic Transmission, Transfection, alpha-Synuclein
Check for Full Text / PubMed Unique Identifier (PMID): 17156375
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