Liddle's syndrome: A novel mouse Nedd4 isoform regulates the activity of the epithelial Na+ channel

The epithelial Na+ channel (ENaC), which plays an essential role in renal N a+ handling, is composed of three subunits (alpha beta gamma), each contain ing a conserved PY motif at the C terminus. In Liddle's syndrome, an inheri ted form of salt-sensitive hypertension, the PY motifs of either beta or ga mma ENaC are deleted or modified. We have recently shown that a ubiquitin-p rotein ligase Nedd4 binds via its WW domains to these PY motifs on ENaC, th at ENaC is regulated by ubiquitination, and that Xenopus laevis Nedd4 (xNed d4) controls the cell surface pool of ENaC when coexpressed in Xenopus oocy tes. Interestingly, Naf transporting cells, derived from mouse cortical col lecting duct, express two different Nedd4 isoforms. which we have termed mN edd4-1 and mNedd4-2. Only mNedd4-2, which is orthologous to xNedd4, but not mNedd4-1. is able to regulate ENaC activity, and this property correlates with the capability to bind to the ENaC complex. Hence. Nedd4-2 may be enco ded by a novel susceptibility gene for arterial hypertension.