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Previous Article | Next Article
The Journal of Neuroscience, March 1, 2003, 23(5):1697
A Regulated Interaction of Syntaxin 1A with the Antidepressant-Sensitive Norepinephrine Transporter Establishes Catecholamine Clearance Capacity
Uhna Sung1, *, Subramaniam Apparsundaram1, *, Aurelio Galli2, Kristopher M. Kahlig2, Valentina Savchenko1, Sally Schroeter1, Michael W. Quick3, and Randy D. Blakely1 1 Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548, 2 Department of Pharmacology, University of Texas at San Antonio, San Antonio, Texas 78249, and 3 Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
Norepinephrine (NE) transporters (NETs) terminate noradrenergic synaptic transmission and represent a major therapeutic target for antidepressant medications. NETs and related transporters are under intrinsic regulation by receptor and kinase-linked pathways, and clarification of these pathways may suggest candidates for the development of novel therapeutic approaches. Syntaxin 1A, a presynaptic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, interacts with NET and modulates NET intrinsic activity. NETs colocalize with and bind to syntaxin 1A in both native preparations and heterologous systems. Protein kinase C activation disrupts surface NET/syntaxin 1A interactions and downregulates NET activity in a syntaxin-dependent manner. Syntaxin 1A binds the NH2 terminal domain of NET, and a deletion of this domain both eliminates NET/syntaxin 1A associations and prevents phorbol ester-triggered NET downregulation. Whereas syntaxin 1A supports the surface trafficking of NET proteins, its direct interaction with NET limits transporter catalytic function. These two contradictory roles of syntaxin 1A on NET appear to be linked and reveal a dynamic cycle of interactions that allow for the coordinated control between NE release and reuptake.
Key words: catecholamine; norepinephrine; antidepressant; transport; syntaxin 1A; phorbol ester; surface trafficking
* U.S. and S.A. contributed equally to this work.
Copyright © 2003 Society for Neuroscience 0270-6474/03/2351697-13$05.00/0
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