Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination

• Published in: Kidney international Vol. 57; no. 3; pp. 809 - 815
• Main Authors: Staub, Olivier, Abriel, Hugues, Plant, Pamela, Ishikawa, Toru, Kanelis, Voula, Saleki, Reza, Horisberger, Jean-Daniel, Schild, Laurent, Rotin, Daniela
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01-03-2000; Nature Publishing; Elsevier Limited
• Subjects: Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; C2 domain; Calcium - physiology; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - physiology; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; ENaC channels; Endosomal Sorting Complexes Required for Transport; Epithelial Sodium Channels; Epithelium - metabolism; Humans; Hypertension - genetics; Hypertension - metabolism; Hypertension - physiopathology; Liddle's syndrome; Ligases - chemistry; Ligases - physiology; Medical sciences; Nedd4 Ubiquitin Protein Ligases; PY motif; Sodium Channels - metabolism; ubiquitin protein ligase; Ubiquitin-Protein Ligases; Ubiquitins - metabolism; WW domain; Liddle's syndrome; C2 domain; ubiquitin protein ligase; ENaC channels; WW domain; PY motif; Human; Hypertension; Genetic marker; Pathophysiology; Lung; Cardiovascular disease; Ionic channel; Genetic determinism; Congenital disease; Kidney; Calcium ion; Sodium ion; Epithelial cell; Colon; Molecular biology; Membrane channel
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1046/j.1523-1755.2000.00919.x

Regulation of the endothelial Na+ channel by Nedd4 and by ubiquitination. The epithelial Na+ channel (ENaC) is comprised of three subunits, α, β and γ, and plays an essential role in Na+ and fluid absorption in the kidney, colon and lung. We had identified proline-rich sequences at the C termini of αβγENaC, which include the sequence PPxY, the PY motif. This sequence in β or γENaC is deleted or mutated in Liddle's syndrome, a hereditary form of arterial hypertension. Our previous work demonstrated that these PY motifs bind to the WW domains of Nedd4, a ubiquitin protein ligase containing a C2 domain, three or four WW domains and a ubiquitin protein ligase Hect domain. Accordingly, we have recently demonstrated that Nedd4 regulates ENaC function by controlling the number of channels at the cell surface, that this regulation is impaired in ENaC bearing Liddle's syndrome mutations, and that ENaC stability and function are regulated by ubiquitination. The C2 domain is responsible for localizing Nedd4 to the plasma membrane in a Ca2+-dependent manner, and in polarized epithelial MDCK cells this localization is primarily apical. In accordance, electrophysiological characterization of ENaC expressed in MDCK cells revealed inhibition of channel activity by elevated intracellular Ca2+ levels. Thus, in response to Ca2+, Nedd4 may be mobilized to the apical membrane via its C2 domain, where it binds ENaC via Nedd4-WW:ENaC–PY motifs' interactions, leading to ubiquitination of the channel by the Nedd4-Hect domain and subsequent channel endocytosis and lysosomal degradation. This process may be at least partially impaired in Liddle's syndrome due to reduced Nedd4 binding, leading to increased retention of ENaC at the cell surface.