A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity.
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.
Sung
Uhna
U
Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548, USA.
Apparsundaram
Subramaniam
S
Galli
Aurelio
A
Kahlig
Kristopher M
KM
Savchenko
Valentina
V
Schroeter
Sally
S
Quick
Michael W
MW
Blakely
Randy D
RD
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001905:Botulinum Toxins / Q000494:pharmacology; D001923:Brain Chemistry; D002395:Catecholamines / Q000378:metabolism* / Q000493:pharmacokinetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050600:SNARE Proteins; D017384:Sequence Deletion; D027981:Symporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013574:Synaptosomes / Q000737:chemistry / Q000378:metabolism; D050827:Syntaxin 1; D014649:Vas Deferens / Q000737:chemistry / Q000378:metabolism; D033921:Vesicular Transport Proteins
D000928:Antidepressive Agents; D000954:Antigens, Surface; D002395:Catecholamines; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D016376:Oligonucleotides, Antisense; D011993:Recombinant Fusion Proteins; C493227:SLC6A2 protein, human; D050600:SNARE Proteins; C494212:STX1A protein, human; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; C494214:Stx1a protein, mouse; C494213:Stx1a protein, rat; D027981:Symporters; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins; D001905:Botulinum Toxins; C096324:botulinum toxin type C; D009638:Norepinephrine