Meta-Biol

• Pathways

Amiloride-sensitive sodium channels (SCNNs, aka ENaCs, epithelial Na+ channels, non voltage-gated sodium channels) comprises three subunits (alpha, beta and gamma) and plays an essential role in Na+ and fluid absorption in the kidney, colon and lung. The number of channels at the cell's surface (consequently its function) can be regulated. This is achieved by ubiquitination of SCNN via E3 ubiquitin-protein ligases (NED4L and WPP1) (Staub et al. 2000, Farr et al. 2000). NED4L/WPP1 is found in a signaling complex including Raf1 (RAF proto-oncogene serine/threonine-protein kinase), SGK (serum/glucocorticoid-regulated kinase) and GILZ (glucocorticoid-induced leucine zipper protein, TSC22D3) (Soundararajan et al. 2009). Ubiquitinated SCNN (Ub-SCNN) is targeted for degradation so a lesser number of channels are present at the cell surface, reducing the amount of Na+ absorption. Proline-rich sequences at the C-terminus of SCNNs include the PY motif containing a PPxY sequence. PY motifs bind WW domains of NED4L/WPP1. Protein kinases with no lysine K (WNKs) can activate SCNN activity by interacting non-enzymatically with the signaling complex, specifically SGK although the mechanism is unknown (Heise et al. 2010).