Plasmin Activates Epithelial Na+ Channels by Cleaving the γ Subunit

• Published in: The Journal of biological chemistry 2008-12, Vol.283 (52), p.36586-36591
• Main Authors: Passero, Christopher J., Mueller, Gunhild M., Rondon-Berrios, Helbert, Tofovic, Stevan P., Hughey, Rebecca P., Kleyman, Thomas R.
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Dogs; Epithelial Sodium Channels - metabolism; Fibrinolysin - metabolism; Furin - metabolism; Humans; Male; Membrane Transport, Structure, Function, and Biogenesis; Mice; Mutagenesis, Site-Directed; Oocytes - metabolism; Protein Structure, Tertiary; Proteinuria - metabolism; Rats; Xenopus
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M805676200

Proteolytic processing of epithelial sodium channel (ENaC) subunits occurs as channels mature within the biosynthetic pathway. The proteolytic processing events of the α and γ subunits are associated with channel activation. Furin cleaves the α subunit ectodomain at two sites, releasing an inhibitory tract and activating the channel. However, furin cleaves the γ subunit ectodomain only once. A second distal cleavage in the γ subunit induced by other proteases, such as prostasin and elastase, is required to release a second inhibitory tract and further activate the channel. We found that the serine protease plasmin activates ENaC in association with inducing cleavage of the γ subunit at γLys194, a site distal to the furin site. A γK194A mutant prevented both plasmin-dependent activation of ENaC and plasmin-dependent production of a unique 70-kDa carboxyl-terminal γ subunit cleavage fragment. Plasmin-dependent cleavage and activation of ENaC may have a role in extracellular volume expansion in human disorders associated with proteinuria, as filtered plasminogen may be processed by urokinase, released from renal tubular epithelium, to generate active plasmin.