Does the cytosolic amino ‐terminus of γ‐ENaC function as a nuclear signaling molecule?

Abstract

Functional ENaC is in the apical plasma membrane of epithelial cells where it's activity is limiting for Na+ (re)absorption and thus, important for electrolyte balance. Enzymes that cleave the channel modify ENaC: including release of the N‐terminal portion of γ‐ENaC. This post‐translational modification increases ENaC activity by increasing channel open probability; however, the role of the section of ENaC cleaved from the core of the channel remains unclear. We previously showed that the amino‐terminal portion of γ‐ENaC when expressed alone targets to the nucleus rather than the plasma membrane. This leads us to wonder whether cleavage of ENaC resulting in release of the N‐terminus of γ‐ENaC results in both an acute activation of the channel and a secondary activation of a nuclear signaling event, similar to Notch signaling and release of the intracellular portion of polycystin. We find that the N‐terminal tail of γ‐ENaC targets to the nucleus decreasing activity of membrane resident channels in a dose‐dependent manner. This is in contrast to the carboxy‐terminal portion of this subunit that does not translocate to the nucleus or affect channel activity. These early results are consistent with the idea that post‐translation modification of ENaC by proteases has two effects: an acute activation of the channel and initiation of a negative‐feedback pathway involving nuclear signaling by the cleaved portion of ENaC.