Back to Search
Start Over
Rab11 supports amphetamine-stimulated norepinephrine transporter trafficking.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2010 Jun 09; Vol. 30 (23), pp. 7863-77. - Publication Year :
- 2010
-
Abstract
- The norepinephrine transporter (NET) is a presynaptic plasma membrane protein that mediates reuptake of synaptically released norepinephrine. NET is also a major target for medications used for the treatment of depression, attention deficit/hyperactivity disorder, narcolepsy, and obesity. NET is regulated by numerous mechanisms, including catalytic activation and membrane trafficking. Amphetamine (AMPH), a psychostimulant and NET substrate, has also been shown to induce NET trafficking. However, neither the molecular basis nor the nature of the relevant membrane compartments of AMPH-modulated NET trafficking has been defined. Indeed, direct visualization of drug-modulated NET trafficking in neurons has yet to be demonstrated. In this study, we used a recently developed NET antibody and the presence of large presynaptic boutons in sympathetic neurons to examine basal and AMPH-modulated NET trafficking. Specifically, we establish a role for Rab11 in AMPH-induced NET trafficking. First, we found that, in cortical slices, AMPH induces a reduction in surface NET. Next, we observed AMPH-induced accumulation and colocalization of NET with Rab11a and Rab4 in presynaptic boutons of cultured neurons. Using tagged proteins, we demonstrated that NET and a truncated Rab11 effector (FIP2DeltaC2) do not redistribute in synchrony, whereas NET and wild-type Rab11a do. Analysis of various Rab11a/b mutants further demonstrates that Rab11 regulates NET trafficking. Expression of the truncated Rab11a effector (FIP2DeltaC2) attenuates endogenous Rab11 function and prevented AMPH-induced NET internalization as does GDP-locked Rab4 S22N. Our data demonstrate that AMPH leads to an increase of NET in endosomes of single boutons and varicosities in a Rab11-dependent manner.
- Subjects :
- Animals
Biotinylation
Cells, Cultured
Fluorescent Antibody Technique
Ganglia, Sympathetic cytology
Mice
Mice, Inbred C57BL
Microscopy, Confocal
Mutation
Neurons drug effects
Protein Transport
Rats
Signal Transduction
Synaptic Vesicles metabolism
rab4 GTP-Binding Proteins metabolism
Adrenergic Agents pharmacology
Amphetamine pharmacology
Carrier Proteins metabolism
Membrane Proteins metabolism
Neurons metabolism
Norepinephrine Plasma Membrane Transport Proteins metabolism
Synaptic Vesicles drug effects
rab GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 30
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 20534835
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.4574-09.2010