ABSTRACT
The epithelial sodium channel (ENaC) is a sodium-selective and constitutively active ion channel that is a key regulator of vertebrate sodium and, consequently, water homeostasis. There are four ENaC subunits (ʹ, ʹ, ʹ, ʹ), which can form heterotrimeric subunit assemblies yielding functionally different ENaC isoforms. Canonical ENaC is found in epithelial tissues where it contributes to the control of transepithelial sodium absorption, indirectly modulating potassium and proton excretion. In addition, ENaC expression has been shown in non-epithelial tissues where its function is less understood. ENaC activity is regulated by a complex network involving the hormonal control of subunit gene expression, posttranslational modifications, kinase-mediated control of channel trafficking to and from the plasma membrane, and the control of channel open probability in response to multiple intra- and extracellular stimuli. Dysregulated control of ENaC activity is associated with severe human diseases, including hypertension, renal and lung diseases. This chapter summarizes the key concepts of ENaC function and regulation in health and disease. Current and future challenges include resolving ENaC gating mechanisms, better defining the role of ENaC in non-epithelial tissues and elucidating the physiology and pathophysiology of ENaCs isoforms containing different subunit combinations.
