title: Plasmin activates epithelial Na+ channels by cleaving the gamma subunit.
abstract: Proteolytic processing of epithelial sodium channel (ENaC) subunits occurs as channels mature within the biosynthetic pathway. The proteolytic processing events of the alpha and gamma subunits are associated with channel activation. Furin cleaves the alpha subunit ectodomain at two sites, releasing an inhibitory tract and activating the channel. However, furin cleaves the gamma subunit ectodomain only once. A second distal cleavage in the gamma 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 gamma subunit at gammaLys194, a site distal to the furin site. A gammaK194A mutant prevented both plasmin-dependent activation of ENaC and plasmin-dependent production of a unique 70-kDa carboxyl-terminal gamma 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.
authors.affiliation: Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Passero
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Mueller
authors.forename: Helbert
authors.initials: H
authors.lastname: Rondon-Berrios
authors.forename: Stevan P
authors.initials: SP
authors.lastname: Tofovic
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Hughey
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kleyman
mesh_terms: D000818:Animals; D001665:Binding Sites; D004285:Dogs; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism*; D045683:Furin / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D014981:Xenopus
chemical_list: D053503:Epithelial Sodium Channels; D005341:Fibrinolysin; D045683:Furin