Role of proteolysis in the activation of epithelial sodium channels

Purpose of review Epithelial sodium channels mediate Na+ transport across high resistance, Na+-transporting epithelia. This review describes recent findings that indicate that epithelial sodium channels are activated by the proteolytic release of inhibitory pepticles from the a and gamma subunits. Recent findings Non-cleaved channels have a low intrinsic open probability that may reflect enhanced channel inhibition by external Na+ - a process referred to as Na+ self-inhibition. Cleavage at a minimum of two sites within the alpha or gamma subunits is required to activate the channel, presumably by releasing inhibitory fragments. The extent of epithelial sodium channel proteolysis is dependent on channel residency time at the plasma membrane, as well as on the balance between levels of expression of proteases that activate epithelial sodium channels and inhibitors of these proteases. Regulated epithelial sodium channel proteolysis has been observed in rat kidney and in human airway epithelia. Summary Proteolysis of epithelial sodium channel subunits plays a key role in modulating epithelial sodium channel activity through changes in channel open probability.