Epithelial Na + channel (ENaC) activity is stimulated by proteolysis of its a and g subunits, which liberates embedded autoinhibitory tracts in the channel’s extracellular region. During biosynthesis, the pro-protein convertase furin cleaves the a subunit twice at consensus sites flanking its inhibitory tract. For the g subunit, furin cleaves once at a site proximal to the inhibitory tract, while a secondary protease cleaves distally after the channel reaches the plasma membrane. Recent work from our lab showed that disruption of furin consensus sites in either the a or g subunit produces a mild phenotype in mice, despite a wealth of evidence that furin dependent cleavage is critical for channel activation in vitro. To explore this mechanism further, we generated mice that lack furin consensus sites in both the a and g subunits in combination (aF2MbgF1M mice). We found that under dietary Na + restriction, aF2MbgF1M mice showed a compensatory increase in ENaC protein expression in the kidney and distal colon, in association with markedly higher aldosterone levels compared to wild type (WT) mice. However, total ENaC activity was similar between Na + -restricted WT and aF2MbgF1M mice as assessed by benzamil-sensitive natriuresis and amiloride-sensitive ISC in the distal colon. Following a benzamil challenge under Na + restriction, aF2MbgF1M mice displayed greater volume depletion than WT mice, including significantly increased blood hematocrit and hemoglobin levels, as well as dramatically higher aldosterone levels. ENaC subunit expression in the kidney and distal colon was also significantly increased following benzamil treatment. Under all experimental conditions, blood electrolyte levels were similar between WT and aF2MbgF1M mice. Together, these data suggest that disruption of furin consensus sites in ENaC’s a and g subunits likely impairs channel function. However, ENaC activity is preserved at the whole-organ level, presumably through aldosterone-dependent compensation, such that homeostasis is maintained in aF2MbgF1M mice during Na + restriction. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Nickerson et al. (Fri,) studied this question.