Noncoordinate regulation of ENaC: paradigm lost?

The epithelial sodium channel (ENaC) is composed of the three homologous subunits alpha, beta, and gamma. The basic oligomerization process inferred from all studies in heterologous systems is preferential assembly of the three subunits into a single oligomeric form. However, there is also considerable evidence that channels composed of only alpha-, alphabeta-, or alphagamma-subunits can form under some circumstances and that individual subunits expressed in heterologous systems can traffic to the cell membrane. In cells that express endogenous ENaC, the three subunits are often synthesized in a differential fashion, with one or two subunits expressed constitutively while the other(s) are induced by different physiological stimuli in parallel with increased ENaC activity. This phenomenon, which we term noncoordinate regulation, has been observed for both whole cell and apical membrane ENaC subunit expression. Several other heteromeric membrane proteins have also been observed to have differential rates of either turnover or trafficking of individual subunits after biosynthesis and membrane localization. Here, we examine the possibility that noncoordinate regulation of ENaC subunits may represent another mechanism in the arsenal of physiological responses to diverse stimuli.