ENaC at the cutting edge: regulation of epithelial sodium channels by proteases

Abstract

Epithelial Na+ channels facilitate the transport of Na+ across high resistance epithelia. Proteolytic cleavage has an important role in regulating the activity of these channels by increasing their open probability. Specific proteases have been shown to activate epithelial Na+ channels by cleaving channel subunits at defined sites within their extracellular domains. This minireview addresses the mechanisms by which proteases activate this channel and the question of why proteolysis has evolved as a mechanism of channel activation.

FIGURE 1.

Linear models of the ENaC subunits. The cytoplasmic N-terminal (Nt) and C-terminal (Ct) tails, the first (M1) and second (M2) transmembrane domains, the large extracellular loop (ECL), and the predicted finger and thumb domains are denoted for the three subunits. The sites for α subunit cleavage by furin and γ subunit cleavage by furin, prostasin (CAP1), CAP2, elastase (neutrophil and pancreatic), and plasmin are within the finger domain in the large extracellular loop. This alignment also reveals that the finger domain of the β subunit (i) lacks the consensus motifs for protease recognition, (ii) has additional sites for N-linked glycan addition, and (iii) has an additional Cys pair. aa, amino acids.

FIGURE 2.

Structure of an ASIC1 subunit. The extracellular domain of ASIC1 is a highly ordered structure that resembles an outstretched hand containing a ball (15). Defined subdomains are highlighted. Sites of proteolysis are primarily within the corresponding finger domain of ENaC. TM1 and TM2, first and second transmembrane domains.