The mechanisms by which epithelial Na⁺ channels are controlled
A Dinudom, P Komwatana, A Srijunbarl, A Sanchez-Perez, DI Cook
collaborators: S Kumar, K Harvey, Inst for Medical & Veterinary Science, Adelaide

The progress we made in 1997 in elucidating the mechanisms by which epithelial Na⁺ channels are controlled is shown in the diagram below. We demonstrated that intracellular Na⁺ down-regulates the activity of epithelial Na⁺ channels by binding to a specific intracellular receptor for Na⁺ that is sensitive to amiloride and related compounds such as dimethylamiloride and enzimidazolylguanidinium. We further showed that the Na ⁺ effects are mediated by the G_o protein, whereas the effects of intracellular Cl ^-are mediated by G_i2. Finally, in the collaboration indicated we showed that control by intracellular Na⁺ of the channel was mediated by the protein Nedd4 which acts by ubiquinating the Na ⁺ channel. This is the first time that animal cells have been shown to contain a receptor for intracellular Na ⁺.

Our demonstration that Nedd4 mediates the effects of intracellular Na⁺ on the Na⁺ channels also provides an explanation for the increased Na⁺ channel activity that is observed in the autosomal dominant form of hypertension, Liddle's syndrome, in which critical Nedd4 binding sites in the COH terminal of the Na ⁺ channel are mutated.