QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.106.026690v1 71/1/230    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dipace, C. Articles by Galli, A. Search for Related Content PubMed PubMed Citation Articles by Dipace, C. Articles by Galli, A.

Amphetamine Induces a Calcium/Calmodulin-Dependent Protein Kinase II-Dependent Reduction in Norepinephrine Transporter Surface Expression Linked to Changes in Syntaxin 1A/Transporter Complexes

Department of Molecular Physiology and Biophysics (C.D., F.B., A.G.), Center for Molecular Neuroscience (C.D., U.S., F.B., R.D.B., A.G.), and Department of Pharmacology (U.S., R.D.B.), Vanderbilt University, Nashville, Tennessee

Norepinephrine (NE) transporters (NETs) are high-affinity transport proteins that mediate the synaptic clearance of NE after vesicular release. NETs represent a major therapeutic target for antidepressants and are targets of multiple psychostimulants including amphetamine (AMPH) and cocaine. Recently, we demonstrated that syntaxin 1A (SYN1A) regulates NET surface expression and, through binding to the transporter's NH₂ terminus, regulates transporter catalytic function. AMPH induces NE efflux and may also regulate transporter trafficking. We monitored NET distribution and function in catecholaminergic cell lines (CAD) stably transfected with either full-length human NET (CAD-hNET) or with an hNET N-terminal deletion (CAD-hNET_28-47 cells). In hNET-CAD cells, AMPH causes a slow and small reduction of surface hNET with a modest increase in hNET/SYN1A associations at the plasma membrane. In contrast, in CAD-hNET_28-47 cells, AMPH induces a rapid and substantial reduction in surface hNET_28-47 accompanied by a large increase in plasma membrane hNET_28-47/SYN1A complexes. We also found that AMPH in CAD-hNET_28-47 cells induces a robust increase in cytosolic Ca²⁺ and concomitant activation of calcium/calmodulin-dependent protein kinase II (CaMKII). Inhibition of either the increase in intracellular Ca²⁺ or CaMKII activity blocks AMPH-stimulated hNET_28-47 trafficking and the formation of hNET_28-47/SYN1A complexes. Here, we demonstrate that AMPH stimulation of CAMKII stabilizes an hNET/SYN1A complex. This hNET/SYN1A complex rapidly redistributes, upon AMPH treatment, when mechanisms supported by the transporter's NH₂ terminus are eliminated.

Address correspondence to: Dr. Aurelio Galli, Department of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, Vanderbilt University Medical Center, 465 21st Avenue South, 7124A Medical Research Building III, Nashville, TN 37232. E-mail: aurelio.galli{at}vanderbilt.edu

This article has been cited by other articles:

				F. Binda, C. Dipace, E. Bowton, S. D. Robertson, B. J. Lute, J. U. Fog, M. Zhang, N. Sen, R. J. Colbran, M. E. Gnegy, et al. Syntaxin 1A Interaction with the Dopamine Transporter Promotes Amphetamine-Induced Dopamine Efflux Mol. Pharmacol., October 1, 2008; 74(4): 1101 - 1108. [Abstract] [Full Text] [PDF]