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Ubiquitylation of voltage-gated sodium channels.
Journal article

Ubiquitylation of voltage-gated sodium channels.

  • Laedermann CJ Department of Clinical Research, University of Bern, Murtenstrasse, 35, 3010, Bern, Switzerland, Cedric.Laedermann@unil.ch.
  • Decosterd I
  • Abriel H
  • 2014-04-17
Published in:
  • Handbook of experimental pharmacology. - 2014
Action Potentials
Animals
Endosomal Sorting Complexes Required for Transport
Epithelial Sodium Channels
Humans
Ion Channel Gating
Nedd4 Ubiquitin Protein Ligases
Protein Binding
Protein Interaction Domains and Motifs
Protein Isoforms
Signal Transduction
Sodium
Ubiquitin-Protein Ligases
Ubiquitination
Voltage-Gated Sodium Channels
English Ion channel proteins are regulated by different types of posttranslational modifications. The focus of this review is the regulation of voltage-gated sodium channels (Navs) upon their ubiquitylation. The amiloride-sensitive epithelial sodium channel (ENaC) was the first ion channel shown to be regulated upon ubiquitylation. This modification results from the binding of ubiquitin ligase from the Nedd4 family to a protein-protein interaction domain, known as the PY motif, in the ENaC subunits. Many of the Navs have similar PY motifs, which have been demonstrated to be targets of Nedd4-dependent ubiquitylation, tagging them for internalization from the cell surface. The role of Nedd4-dependent regulation of the Nav membrane density in physiology and disease remains poorly understood. Two recent studies have provided evidence that Nedd4-2 is downregulated in dorsal root ganglion (DRG) neurons in both rat and mouse models of nerve injury-induced neuropathic pain. Using two different mouse models, one with a specific knockout of Nedd4-2 in sensory neurons and another where Nedd4-2 was overexpressed with the use of viral vectors, it was demonstrated that the neuropathy-linked neuronal hyperexcitability was the result of Nav1.7 and Nav1.8 overexpression due to Nedd4-2 downregulation. These studies provided the first in vivo evidence of the role of Nedd4-2-dependent regulation of Nav channels in a disease state. This ubiquitylation pathway may be involved in the development of symptoms and diseases linked to Nav-dependent hyperexcitability, such as pain, cardiac arrhythmias, epilepsy, migraine, and myotonias.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/183268
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