Kinases as Targets for ENaC Regulation

Amiloride-sensitive epithelial sodium channels (ENaCs) transport Na+ and are essential for salt and fluid homeostasis across epithelial tissues. Several pathological conditions of renal and pulmonary tissues are associated with abnormal ENaC function. The signalling pathways that regulate ENaC activity utilise a number of kinases. Over recent years, more have been identified and their mechanisms of action expanded. The functions of SGK and PKA are the best understood and both up-regulate ENaC activity. SGK is an important target of PI3K via PDK1 and TORC2 whilst PKA is linked with the activity of other kinases that have complementary effects. CK2, GRK2, IKKβ and PKD1 also up-regulate ENaC. In contrast, PKC, ERK1/2 and AMPK are inhibitory. Two key convergence targets for kinase action persist. These are phosphorylation of Nedd4-2 and the β and γ subunits of ENaC. Depending on the sites targeted, phosphorylation predominantly promotes or decreases association between these proteins to regulate ENaC retrieval and its subsequent abundance in the membrane. Alternative emerging targets include proteins involved in the translocation and recycling of ENaC channels to the membrane. Targeting kinases to modify ENaC function in vivo has shown some promise. Inactivation of SGK has produced mild but positive effects on renal function. Activating PKA has shown potential in lung pathologies. Inhibition of PI3K and PKB may prove useful in diabetic related alterations in renal Na+ handling, as could activation of AMPK, which may also have potential in the treatment of pulmonary pathologies associated with elevated ENaC activity.