ENaC activation by intra- and extracellular proteases. (A) Cartoon illustration of ENaC cleavage by furin within the trans-Golgi network and extracellular proteases at the cell surface. PO, open probability. (B) Peptide sequences of the α- and γ-subunits of human ENaC showing the regions containing the inhibitory peptides within the extracellular loop. Furin consensus sites are shown in blue; the inhibitory peptides [38] are shown in red. The figure shows extracellular proteases cleaving the γ-subunit whose cleavage sites have been identified by mutagenesis studies [48,72,73]: Serine proteases are shown in magenta, cysteine protease in orange, and metalloprotease in brown. CAP, channel-activating protease (alternative name for the indicated proteases); FSAP-SPD, factor VII activating protease—serine protease domain. Reproduced from [74] (Figure 1); Copyright © The Authors, 2021; published by Springer, Berlin, New York.