SPLUNC1 expression reduces surface levels of the epithelial sodium channel (ENaC) in Xenopus laevis oocytes.
Throughout the body, the epithelial Na(+) channel (ENaC) plays a critical role in salt and liquid homeostasis. In cystic fibrosis airways, for instance, improper regulation of ENaC results in hyperabsorption of sodium that causes dehydration of airway surface liquid. This dysregulation then contributes to mucus stasis and chronic lung infections. ENaC is known to undergo proteolytic cleavage, which is required for its ability to conduct Na(+) ions. We have previously shown that the short, palate lung and nasal epithelial clone (SPLUNC1) binds to and inhibits ENaC in both airway epithelia and in Xenopus laevis oocytes. In this study, we found that SPLUNC1 was more potent at inhibiting ENaC than either SPLUNC2 or long PLUNC1 (LPLUNC1), two other PLUNC family proteins that are also expressed in airway epithelia. Furthermore, we were able to shed light on the potential mechanism of SPLUNC1's inhibition of ENaC. While SPLUNC1 did not inhibit proteolytic activity of trypsin, it significantly reduced ENaC currents by reducing the number of ENaCs in the plasma membrane. A better understanding of ENaC's regulation by endogenous inhibitors may aid in the development of novel therapies designed to inhibit hyperactive ENaC in cystic fibrosis epithelia.
Rollins
Brett M
BM
Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina, Chapel Hill, NC, USA.
Garcia-Caballero
Agustin
A
Stutts
M Jackson
MJ
Tarran
Robert
R
D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials; D009865:Oocytes / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012471:Salivary Proteins and Peptides / Q000378:metabolism; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism; D014982:Xenopus laevis
C485599:BPIFA1 protein, human; C045623:BPIFA2 protein, human; D053503:Epithelial Sodium Channels; D006023:Glycoproteins; D010750:Phosphoproteins; C507045:SCNN1A protein, human; C507048:SCNN1B protein, human; C507052:SCNN1G protein, human; D012471:Salivary Proteins and Peptides; D014357:Trypsin