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CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex.

Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) mediate membrane fusion reactions in eukaryotic cells by assembling into complexes that link vesicle-associated SNAREs with SNAREs on target membranes (t-SNAREs). Many SNARE complexes contain two t-SNAREs that form a heterodimer, a putative intermediate in SNARE assembly. Individual t-SNAREs (e.g., syntaxin 1A) also regulate synaptic calcium channels and cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial chloride channel that is defective in cystic fibrosis. Whether the regulation of ion channels by individual t-SNAREs is related to SNARE complex assembly and membrane fusion is unknown. Here we show that CFTR channels are coordinately regulated by two cognate t-SNAREs, SNAP-23 (synaptosome-associated protein of 23 kDa) and syntaxin 1A. SNAP-23 physically associates with CFTR by binding to its amino-terminal tail, a region that modulates channel gating. CFTR-mediated chloride currents are inhibited by introducing excess SNAP-23 into HT29-Cl.19A epithelial cells. Conversely, CFTR activity is stimulated by a SNAP-23 antibody that blocks the binding of this t-SNARE to the CFTR amino-terminal tail. The physical and functional interactions between SNAP-23 and CFTR depend on syntaxin 1A, which binds to both proteins. We conclude that CFTR channels are regulated by a t-SNARE complex that may tune CFTR activity to rates of membrane traffic in epithelial cells.

Pubmed ID: 12209004 RIS Download

Mesh terms: Animals | Antigens, Surface | Binding Sites | COS Cells | Carrier Proteins | Cell Line | Cell Membrane | Cystic Fibrosis Transmembrane Conductance Regulator | Humans | Ion Channel Gating | L Cells (Cell Line) | Macromolecular Substances | Membrane Proteins | Mice | Nerve Tissue Proteins | Patch-Clamp Techniques | Qb-SNARE Proteins | Qc-SNARE Proteins | Recombinant Proteins | SNARE Proteins | Syntaxin 1 | Vesicular Transport Proteins

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Associated grants

  • Agency: NHLBI NIH HHS, Id: HL58341
  • Agency: NIDDK NIH HHS, Id: DK56796
  • Agency: NIDDK NIH HHS, Id: R56 DK056796
  • Agency: NHLBI NIH HHS, Id: R01 HL058341
  • Agency: NIDDK NIH HHS, Id: R01 DK056796

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