The epithelial sodium channel (ENaC) is a heteromultimeric Na+ selective ion channel member of the ENaC/degenerins family of non-voltage gated ion channels. Canonically, ENaC is composed by three analogous subunits ¿, ß and ¿ and represents the rate-limiting step of Na+-reabsorption across tight epithelia. Another subunit, named ¿, is expressed in the nervous system of primates, where its role and regulation are unknown. The ¿-subunit can substitute ¿ and form functional channels either alone or with ß and ¿. ¿-ENaC has been proposed to participate in the transduction of ischemic signals during hypoxia and inflammation. ¿-ENaC exists in two isoforms, ¿1 and ¿2. Pyramidal neurons of the human cortex express either ¿1 or ¿2, with few cells co-expressing both isoforms, which suggest that they may play specific physiological roles. Heterologous expression of ¿1 in Xenopus oocytes led to ~2.5 fold more amiloride-sensitive current than ¿2. The difference in whole-cell current is based on differential plasma membrane abundance between isoforms. Two sequences in the ¿2 N-terminus independently reduced channel abundance in the membrane based on altered insertion rates and without involvement of PY motifs. Since Dynasore did not inhibit ¿-ENaC endocytosis, it is concluded that ¿-ENaC undergoes clathrin-independent endocytosis as opposed to ¿ß¿-ENaC. ¿ß¿-ENaC in the distal nephron is regulated by the serum- and glucocorticoid-induced kinase 1 (SGK1) and a neuronal-specific isoform, SGK1.1, was found to regulate asid sensing ion channel 1 (ASIC1), another member of the ENaC/degenerins family. Here is shown that SGK1.1 is involved in ¿-ENaC regulation. Co-expression of SGK1.1 with ¿-ENaC in Xenopus oocytes leads to enhanced amiloride-sensitive currents when compared to ¿-ENaC currents alone. This effect does not require a PY motif and depends on SGK1.1 phosphorylation activity and binding to phosphatidylinositol 4,5-bisphosphate (PIP2). Further, activation of Phospholipase C abrogates SGK1.1 modulation of ¿-ENaC