Unsolved problems with ENaC: From molecules to mammals

The epithelial Na channel (ENaC) mediates transport of Na+ in the kidney, the colon, the lung, and the sweat and salivary ducts. The activity of these channels is highly regulated and contributes to the maintenance of total body Na+, extracellular fluid volume, and plasma K+. Defects in the channel itself or in its regulation are implicated in hypertension and in other diseases. Despite progress in revealing many aspects of ENaC biology, many important questions remain unanswered. These include the following: What determines the remarkable ion selectivity of the channel? How is the channel directed to the apical plasma membrane? How does aldosterone regulate the channel? What is its role in producing urine with minimal Na+? And to what extent does the channel contribute to essential hypertension, cystic fibrosis, nephrotic syndrome, and liver failure? Here, I will discuss these questions and how they relate to our current understanding of the roles of ENaC in health and disease.