Ubiquitylation of voltage-gated sodium channels.

Laedermann, Cédric J; Decosterd, Isabelle; Abriel, Hugues (2014). Ubiquitylation of voltage-gated sodium channels. In: Ruben, Peter C. (ed.) Voltage Gated Sodium Channels. Handbook of Experimental Pharmacology: Vol. 221 (pp. 231-250). Springer 10.1007/978-3-642-41588-3_11

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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.

Item Type:	Book Section (Book Chapter)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Ionenkanalkrankheiten
UniBE Contributor:	Abriel, Hugues
Subjects:	600 Technology > 610 Medicine & health
ISSN:	0171-2004
ISBN:	978-3-642-41587-6
Series:	Handbook of Experimental Pharmacology
Publisher:	Springer
Language:	English
Submitter:	Verena de Serra Frazao-Bill
Date Deposited:	10 Nov 2014 10:44
Last Modified:	05 Dec 2022 14:38
Publisher DOI:	10.1007/978-3-642-41588-3_11
PubMed ID:	24737239
URI:	https://boris.unibe.ch/id/eprint/60012