A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity.

Sung U, Apparsundaram S, Galli A, Kahlig KM, Savchenko V, Schroeter S, Quick MW, Blakely RD
J Neurosci. 2003 23 (5): 1697-709

PMID: 12629174 · PMCID: PMC6741950

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 NH(2) 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.

MeSH Terms (33)

Animals Antidepressive Agents Antigens, Surface Botulinum Toxins Brain Chemistry Catecholamines Cells, Cultured Enzyme Activation Enzyme Activators Enzyme Inhibitors Humans Male Membrane Proteins Mice Mice, Inbred C57BL Nerve Tissue Proteins Neurons Norepinephrine Norepinephrine Plasma Membrane Transport Proteins Oligonucleotides, Antisense Patch-Clamp Techniques Protein Binding Protein Structure, Tertiary Protein Transport Rats Recombinant Fusion Proteins Sequence Deletion SNARE Proteins Symporters Synaptosomes Syntaxin 1 Vas Deferens Vesicular Transport Proteins

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