Role of snare proteins in CFTR and ENaC trafficking.
The apical membrane ion channels, CFTR and ENaC, undergo regulated trafficking as a means of controlling their plasma membrane density. This provides a mechanism for regulating the Cl and Na conductance properties of epithelial apical membranes, and thus the transepithelial ion transport rates. Physical and functional interactions between these channels and SNARE proteins, in particular syntaxin 1A (S1A), provide a mechanism for linking the known vesicle fusion machinery with this process. In this paper we summarize evidence indicating that the interaction of S1A with CFTR and ENaC reduces channel currents in a syntaxin-isoform-specific manner. The acute cAMP-regulated CFTR trafficking event, which is reported by an increase in membrane capacitance in response to cAMP, is also inhibited by exogenous S1A expression. We tagged both channels with flag epitopes on their extracellular surfaces to monitor their plasma membrane expression as a function of S1A co-expression. The data indicate that the reduction in current caused by S1A is associated with a marked decrease in the amount of CFTR or ENaC detected at the cell surface. These findings suggest that S1A inhibits ion channel insertion into the plasma membrane, either by disrupting the stoichiometry of SNARE protein associations that mediate channel trafficking, or by physically associating with the channels to prevent their insertion. These data link the SNARE machinery to the regulation of apical membrane ion channel density, and suggest that phosphorylation-dependent interactions of these channels with SNARE proteins may acutely regulate this process.
Peters
K W
KW
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Qi
J
J
Johnson
J P
JP
Watkins
S C
SC
Frizzell
R A
RA
D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D053503:Epithelial Sodium Channels; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D050600:SNARE Proteins; D015222:Sodium Channels / Q000378:metabolism*; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins
C505032:CFTR protein, human; D053503:Epithelial Sodium Channels; D008565:Membrane Proteins; D050600:SNARE Proteins; C494212:STX1A protein, human; D015222:Sodium Channels; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator