Regulation of voltage-gated ion channels in excitable cells by the ubiquitin ligases Nedd4 and Nedd4-2

The electrical excitability of neurons is mediated primarily by voltage-gated ion channels, particularly voltage-gated Na+ (Na-V), K+ (K-V) and Cl-(ClC) channels. Cells regulate their electrical excitability by controlling not only the activity, but also the number of individual ion channels in the plasma membrane. There exist several mechanisms for regulating levels of voltage-gated ion channels: transcription and translation, retention and export from the endoplasmic reticulum as well as insertion and retrieval from the plasma membrane. Alterations in voltage-gated ion channel activity, composition and distribution can contribute to the pathophysiology of epilepsy, hypertension, neuropathic and inflammatory pain. One mechanism for retrieval is ubiquitination. Here specific ubiquitin ligases bind to membrane proteins to modulate and regulate their cellular fate. In this review, we focus on Nedd4 and Nedd4-2 ubiquitin ligases and the mechanisms by which they regulate voltage-gated ion channels and describe a novel paradigm on the mechanisms that underpin aberrant ion channel function in neurological disorders.