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Pflugers Arch 2018 Apr 01;4704:649-660. doi: 10.1007/s00424-018-2115-2.
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The phosphorylation site T613 in the β-subunit of rat epithelial Na+ channel (ENaC) modulates channel inhibition by Nedd4-2.

Krueger B , Yang L , Korbmacher C , Rauh R .

The epithelial Na+ channel (ENaC) is a heteromeric channel composed of three subunits (α, β, γ). At the C-terminus of each subunit, a PY-motif allows binding of the ubiquitin ligase Nedd4-2 which plays a key role in promoting ENaC retrieval from the plasma membrane. Phosphorylation of Nedd4-2 by the serum and glucocorticoid-inducible kinase 1 (Sgk1) reduces Nedd4-2 binding to the PY-motifs. In β and γENaC, threonine residues (βT613, γT623) belong to an extracellular signal-regulated kinase (ERK) motif and directly precede the PY-motifs. Thus, phosphorylation of these residues may modulate the interaction of their adjacent PY-motifs with Nedd4-2. In this study, a phosphospecific antibody was used to demonstrate phosphorylation of βT613 in Xenopus laevis oocytes heterologously expressing rat αβγENaC. Treating the oocytes with progesterone to stimulate ERK increased phosphorylation of βT613. Inactivation of the putative phosphorylation sites by mutating both threonine residues to alanine (βT613A/γT623A) increased ENaC-mediated amiloride-sensitive whole-cell currents (ΔIami) and expression of βENaC at the cell surface. Co-expression of Nedd4-2 largely reduced ΔIami in oocytes expressing αβγENaC or channels with mutated PY-motifs in α and γENaC or in α and βENaC. Importantly, the inhibitory effect of co-expressed Nedd4-2 was largely reduced in channels with mutated PY-motifs in α and γENaC when combined with the βT613A mutation but conserved in channels with mutated PY-motifs in α and βENaC combined with the γT623A mutation. These results suggest that phosphorylation and dephosphorylation of βT613 play a prominent role in regulating Nedd4-2-mediated ENaC retrieval from the plasma membrane.

PubMed ID: 29397423
Article link: Pflugers Arch
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: mapk1 nedd4 sgk1
GO keywords: ubiquitin protein ligase activity