Peptide inhibition of ENaC.

Academic Article


  • Liddle's disease is an autosomal dominant form of human hypertension resulting from a basal activation of amiloride-sensitive Na+ channels (ENaC). This channel activation is produced by mutations in the beta- and/or gamma-carboxy-terminal cytoplasmic tails, in many cases causing a truncation of the last 45-76 amino acids. In this study, we tested two hypotheses; first, beta- and gamma-ENaC C-terminal truncation mutants (beta DeltaC and gamma DeltaC), in combination with the wild-type alpha-ENaC subunit, reproduce the Liddle's phenotype at the single channel level, i.e., an increase in open probability (Po), and second, these C-terminal regions of beta- and gamma-ENaC act as intrinsic blockers of this channel. Our results indicate that alpha beta DeltaC gamma DeltaC-rENaC, incorporated into planar lipid bilayers, has a significantly higher single channel Po compared to the wild-type channel (0.85 vs 0.60, respectively), and that 30-mer synthetic peptides corresponding to the C-terminal region of either beta- or gamma-ENaC block the basal-activated channel in a concentration-dependent fashion. Moreover, there was a synergy between the peptides for channel inhibition when added together. We conclude that the increase in macroscopic Na+ reabsorption that occurs in Liddle's disease is at least in part due to an increase in single channel Po and that the cytoplasmic tails of the beta- and gamma-ENaC subunits are important in the modulation of ENaC activity.
  • Published In

  • Biochemistry  Journal
  • Keywords

  • Amino Acid Sequence, Circular Dichroism, Epithelial Sodium Channels, Lipid Bilayers, Models, Chemical, Molecular Sequence Data, Peptide Fragments, Peptides, Sodium Channel Blockers, Sodium Channels, Solutions
  • Digital Object Identifier (doi)

    Author List

  • Ismailov II; Shlyonsky VG; Serpersu EH; Fuller CM; Cheung HC; Muccio D; Berdiev BK; Benos DJ
  • Start Page

  • 354
  • End Page

  • 363
  • Volume

  • 38
  • Issue

  • 1