@article{WichmannVowinkelPernissetal.2018,
  author    = {Lukas Wichmann and Kirsty Sophia Vowinkel and Alexander Perniss and Ivan Manzini and Mike Althaus},
  title     = {Incorporation of the -subunit into the epithelial sodium channel (ENaC) generates protease-resistant ENaCs in Xenopus laevis},
  series   = {The Journal of Biological Chemistry},
  volume    = {293},
  number    = {18},
  publisher = {Elsevier},
  issn      = {0021-9258},
  doi       = {10.1074/jbc.RA118.002543},
  pages     = {6647 -- 6658},
  year      = {2018},
  abstract  = {The epithelial sodium channel (ENaC) is a critical regulator of vertebrate electrolyte homeostasis. ENaC is the only constitutively open ion channel in the degenerin/ENaC protein family, and its expression, membrane abundance, and open probability therefore are tightly controlled. The canonical ENaC is composed of three subunits (, , and ), but a fourth -subunit may replace and form atypical -ENaCs. Using Xenopus laevis as a model, here we found that mRNAs of the - and -subunits are differentially expressed in different tissues and that -ENaC predominantly is present in the urogenital tract. Using whole-cell and single-channel electrophysiology of oocytes expressing Xenopus - or -ENaC, we demonstrate that the presence of the -subunit enhances the amount of current generated by ENaC due to an increased open probability, but also changes current into a transient form. Activity of canonical ENaCs is critically dependent on proteolytic processing of the - and -subunits, and immunoblotting with epitope-tagged ENaC subunits indicated that, unlike -ENaC, the -subunit does not undergo proteolytic maturation by the endogenous protease furin. Furthermore, currents generated by -ENaC were insensitive to activation by extracellular chymotrypsin, and presence of the -subunit prevented cleavage of -ENaC at the cell surface. Our findings suggest that subunit composition constitutes an additional level of ENaC regulation, and we propose that the Xenopus -ENaC subunit represents a functional example that demonstrates the importance of proteolytic maturation during ENaC evolution.},
  language  = {en}
}