Epithelial sodium channels are activated by furin-dependent proteolysis.
Epithelial Na(+) channels (ENaCs) are activated by extracellular trypsin or by co-expression with channel-activating proteases, although there is no direct evidence that these proteases activate ENaC by cleaving the channel. We previously demonstrated that the alpha and gamma subunits of ENaC are cleaved during maturation near consensus sites for furin cleavage. Using site-specific mutagenesis of channel subunits, ENaC expression in furin-deficient cells, and furin-specific inhibitors, we now report that ENaC cleavage correlates with channel activity. Channel activity in furin-deficient cells was rescued by expression of furin. Our data provide the first example of a vertebrate ion channel that is a substrate for furin and whose activity is dependent on its proteolysis.
Hughey
Rebecca P
RP
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Bruns
James B
JB
Kinlough
Carol L
CL
Harkleroad
Keri L
KL
Tong
Qiusheng
Q
Carattino
Marcelo D
MD
Johnson
John P
JP
Stockand
James D
JD
Kleyman
Thomas R
TR
D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004594:Electrophysiology; D010450:Endopeptidases / Q000378:metabolism; D004847:Epithelial Cells / Q000737:chemistry*; D045683:Furin / Q000235:genetics / Q000378:metabolism*; D006868:Hydrolysis; D051379:Mice; D016297:Mutagenesis, Site-Directed; D021122:Protein Subunits / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014981:Xenopus
D021122:Protein Subunits; D015222:Sodium Channels; D001120:Arginine; D010450:Endopeptidases; D045683:Furin