Mecanismos moleculares implicados en la regulación de la función del canal epitelial del sodio delta (delta-enac)

  1. Wesch, Diana Luise
Supervised by:
  1. Diego Álvarez de la Rosa Rodríguez Director
  2. Teresa Giraldez Fernandez Co-director

Defence university: Universidad de La Laguna

Fecha de defensa: 15 December 2011

  1. Walter Stühmer Chair
  2. Veronique Smits Secretary
  3. Rafael Alonso Solís Committee member
  4. Ricardo Borges Jurado Committee member
  5. Miriam Echevarría Committee member
  1. Ciencias Médicas Básicas

Type: Thesis

Teseo: 316221 DIALNET


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.