Article: article from journal or magazin.
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Ubiquitylation of voltage-gated sodium channels.
Handbook of Experimental Pharmacology
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Review Publication Status: ppublish
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.
Action Potentials, Animals, Endosomal Sorting Complexes Required for Transport/chemistry, Endosomal Sorting Complexes Required for Transport/metabolism, Epithelial Sodium Channels/chemistry, Epithelial Sodium Channels/metabolism, Humans, Ion Channel Gating, Protein Binding, Protein Interaction Domains and Motifs, Protein Isoforms, Signal Transduction, Sodium/metabolism, Ubiquitin-Protein Ligases/chemistry, Ubiquitin-Protein Ligases/metabolism, Ubiquitination, Voltage-Gated Sodium Channels/chemistry, Voltage-Gated Sodium Channels/metabolism
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