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Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2

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dc.contributor.authorFotia, A.
dc.contributor.authorEkberg, J.
dc.contributor.authorAdams, D.
dc.contributor.authorCook, D.
dc.contributor.authorPoronnik, P.
dc.contributor.authorKumar, S.
dc.date.issued2004
dc.description.abstractNedd4 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.
dc.identifier.citationJournal of Biological Chemistry, 2004; 279(28):28930-28935
dc.identifier.doi10.1074/jbc.M402820200
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.orcidKumar, S. [0000-0001-7126-9814]
dc.identifier.urihttp://hdl.handle.net/2440/9550
dc.language.isoen
dc.publisherAmer Soc Biochemistry Molecular Biology Inc
dc.source.urihttps://doi.org/10.1074/jbc.m402820200
dc.subjectOocytes
dc.subjectNeurons
dc.subjectAnimals
dc.subjectXenopus
dc.subjectHumans
dc.subjectMice
dc.subjectUbiquitin-Protein Ligases
dc.subjectXenopus Proteins
dc.subjectSodium Channels
dc.subjectRecombinant Fusion Proteins
dc.subjectPatch-Clamp Techniques
dc.subjectMutagenesis, Site-Directed
dc.subjectSequence Alignment
dc.subjectAmino Acid Sequence
dc.subjectProtein Structure, Tertiary
dc.subjectProtein Binding
dc.subjectSequence Homology, Amino Acid
dc.subjectMolecular Sequence Data
dc.subjectEndosomal Sorting Complexes Required for Transport
dc.subjectNedd4 Ubiquitin Protein Ligases
dc.titleRegulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2
dc.typeJournal article
pubs.publication-statusPublished

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