title: Regulation of the cardiac voltage-gated Na+ channel (H1) by the ubiquitin-protein ligase Nedd4.
abstract: The cardiac voltage-gated Na+ channel H1, involved in the generation of cardiac action potential, contains a C-terminal PY motif (xPPxY). Since PY motifs are known ligands to WW domains, we investigated their role for H1 regulation and the possible involvement of the WW domain containing ubiquitin-protein ligase Nedd4, taking advantage of the Xenopus oocyte system. Mutation of the PY motif leads to higher peak currents when compared to wild-type channel. Moreover, co-expression of Nedd4 reduced the peak currents, whereas an enzymatically inactive Nedd4 mutant increased them, likely by competing with endogenous Nedd4. The effect of Nedd4 was not observed in the PY motif mutated channel or in the skeletal muscle voltage-gated Na+ channel, which lacks a PY motif. We conclude that H1 may be regulated by Nedd4 depending on WW-PY interaction, and on an active ubiquitination site.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Lausanne, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Abriel
authors.forename: E
authors.initials: E
authors.lastname: Kamynina
authors.forename: J D
authors.initials: JD
authors.lastname: Horisberger
authors.forename: O
authors.initials: O
authors.lastname: Staub
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport; D005786:Gene Expression Regulation / Q000502:physiology*; D015640:Ion Channel Gating; D008025:Ligases; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D014981:Xenopus; D029867:Xenopus Proteins
chemical_list: D002135:Calcium-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D015222:Sodium Channels; D029867:Xenopus Proteins; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618482:Nedd4 protein, Xenopus; C000618484:Nedd4 protein, rat; C000618460:nedd4l protein, Xenopus; D044767:Ubiquitin-Protein Ligases; D008025:Ligases