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Type: Journal article
Title: Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2
Author: Fotia, A.
Ekberg, J.
Adams, D.
Cook, D.
Poronnik, P.
Kumar, S.
Citation: Journal of Biological Chemistry, 2004; 279(28):28930-28935
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2004
ISSN: 0021-9258
Abstract: Nedd4 and Nedd4-2 are ubiquitin-protein ligases known to regulate a number of membrane proteins including receptors and ion transporters. Regulation of the epithelial Na(+) channel by Nedd4 and Nedd4-2 is mediated via interactions between the PY motifs of the epithelial sodium channel subunits and the Nedd4/Nedd4-2 WW domains. This example serves as a model for the regulation of other PY motif-containing ion channels by Nedd4 and Nedd4-2. We found that the carboxyl termini of the six voltage-gated Na(+) (Na(v)) channels contain typical PY motifs (PPXY), and a further Na(v) contains a PY motif variant (LPXY). Not only did we demonstrate by Far-Western analysis that Nedd4 and Nedd4-2 interact with the PY motif-containing Na(v) channels, but we also showed that these channels have conserved WW domain binding specificity. We further showed that the carboxyl termini fusion proteins of one central nervous system and one peripheral nervous system-derived Na(+) channel (Na(v)1.2 and Na(v)1.7, respectively) are readily ubiquitinated by Nedd4-2. In Xenopus oocytes, Nedd4-2 strongly inhibited the activities of all three Na(v)s (Na(v)1.2, Na(v)1.7, and Na(v)1.8) tested. Interestingly, Nedd4 suppressed the activity of Na(v)1.2 and Na(v)1.7 but was a poor inhibitor of Na(v)1.8. Our results provide evidence that Nedd4 and Nedd4-2 are likely to be key regulators of specific neuronal Na(v) channels in vivo.
Keywords: Oocytes
Ubiquitin-Protein Ligases
Xenopus Proteins
Sodium Channels
Recombinant Fusion Proteins
Patch-Clamp Techniques
Mutagenesis, Site-Directed
Sequence Alignment
Amino Acid Sequence
Protein Structure, Tertiary
Protein Binding
Sequence Homology, Amino Acid
Molecular Sequence Data
Endosomal Sorting Complexes Required for Transport
Nedd4 Ubiquitin Protein Ligases
DOI: 10.1074/jbc.M402820200
Appears in Collections:Aurora harvest
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