The role of the ENaC-regulatory complex in aldosterone-mediated sodium transport

The mineralocorticoid aldosterone is indispensable for the control of blood pressure and fluid volume in mammals. It acts in large part to increase the abundance and activity of the epithelial Na+ channel (ENaC), which mediates apical Na+ entry in the distal parts of the kidney tubules. Aldosterone acts through the mineralocorticoid receptor to alter the transcription of specific genes, including SGK1 and GILZ1. Recent evidence suggests that these key aldosterone-regulated factors function within a unique multi-protein ENaC-regulatory-complex that governs the net cell surface expression and activity of the channel. Another aldosterone-induced protein, CNK3 (connector enhancer of kinase suppressor of Ras 3), also stimulates ENaC and has all of the features of a scaffolding protein. With these observations in mind, we discuss the possibility that CNK3 coordinates the dynamic assembly of the ENaC-regulatory-complex, and promotes context-appropriate aldosterone signal transduction in the regulation of epithelial Na+ transport.

► The ENaC-regulatory complex (ERC).
► Its composition and function in regulation of ENaC.
► Role of GILZ1 as a key aldosterone-induced modifier of complex composition.
► CNK3 as a molecular scaffold assisting in assembly and functioning of the ERC.
► Hypothetical model for aldosterone-induced ENaC activity.