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Nedd4-2 regulation of voltage-gated ion channels: an update on structure–function relationships and the pathophysiological consequences of dysfunction

Authors Arévalo JC

Received 23 May 2015

Accepted for publication 14 July 2015

Published 18 August 2015 Volume 2015:8 Pages 53—63

DOI https://doi.org/10.2147/JRLCR.S52534

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Pradip Sarkar

Peer reviewer comments 2

Editor who approved publication: Professor Trevor W. Stone


Juan Carlos Arévalo1,2

1Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León, Universidad de Salamanca, 2Institute of Biomedical Research of Salamanca, Salamanca, Spain

Abstract: Neuronal excitability is mediated mainly by voltage-gated ion channels (VGICs), which include voltage-gated Na+, K+, and Cl channels located along the axon and at neuronal synapses. Voltage-gated channels play pivotal roles in the proper functioning of the nervous system because they set the resting membrane potential, initiate and propagate action potentials, and regulate neurotransmitter release. The abnormal activity or misregulation of VGICs caused by mutations has been directly linked to neurological and cardiac diseases. Among other posttranslational modifications, the ubiquitination of VGICs is a key to the regulation of the number of channels in the cell surface, and hence, neuronal excitability. Nedd4-2 is an E3 ubiquitin ligase that ubiquitinates several proteins, including different VGICs. Accordingly, understanding the molecular mechanisms underlying channel regulation will provide insights to design drugs to treat illnesses. The focus of the present review is to provide an update about the regulation of VGICs upon ubiquitination by Nedd4-2 and the relevance of such regulation in the pathophysiological consequences of dysfunction.

Keywords: Nedd4-2, voltage-gated ion channels, disease

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