Cleavage of Sodium Channel Releases Inhibitory Peptide

Science's STKE  11 Jul 2006:
Vol. 2006, Issue 343, pp. tw227
DOI: 10.1126/stke.3432006tw227

Epithelial sodium channels (ENaCs), which are involved in sodium and volume regulation in such organs as lung and kidney, are composed of three subunits: α, β, and γ. Mature ENaCs are cleaved at two sites in the α subunit and one site in the γ subunit, and cleavage of the α subunit is required for activity. Carattino et al. show that furin cleavage of the α subunit releases an inhibitory 26-amino acid peptide, thereby increasing channel open probability. Channel activity of wild-type and cleavage-deficient channels or channels lacking the 26-amino acid domain was measured in oocytes expressing the mouse ENaC subunits. Cleavage was not required for channel activity of mutants lacking the 26-amino acid domain. Indeed, a synthetic form of that 26-mer peptide was sufficient to inhibit channel activity when added to mouse ENaC expressed in oocytes or endogenous ENaC in two cultured cell lines. Single-channel analysis of the wild-type mouse channels expressed in oocytes showed that application of the 26-mer inhibitory peptide altered channel gating with a decrease in channel open probability, which is consistent with the gating of uncleavage immature ENaCs. Inhibition of ENaC activity has therapeutic applications in hypertension and cystic fibrosis. Although the 26-mer peptide is a relatively low-affinity inhibitor, derivatives based on this inhibitor may provide additional therapeutic options.

M. D. Carattino, S. Sheng, J. B. Bruns, J. M. Pilewski, R. P. Hughey, T. R. Kleyman, The epithelial Na+ channel is inhibited by a peptide derived from proteolytic processing of its α subunit. J. Biol. Chem. 281, 18901-18907 (2006). [Abstract] [Full Text]