Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1

Albesa, Maxime; Grilo, Liliana Sintra; Gavillet, Bruno; Abriel, Hugues (2011). Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1. Journal of molecular and cellular cardiology, 51(1), pp. 90-8. Oxford: Elsevier 10.1016/j.yjmcc.2011.03.015

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The voltage-gated cardiac potassium channel hERG1 (human ether-à-gogo-related gene 1) plays a key role in the repolarization phase of the cardiac action potential (AP). Mutations in its gene, KCNH2, can lead to defects in the biosynthesis and maturation of the channel, resulting in congenital long QT syndrome (LQTS). To identify the molecular mechanisms regulating the density of hERG1 channels at the plasma membrane, we investigated channel ubiquitylation by ubiquitin ligase Nedd4-2, a post-translational regulatory mechanism previously linked to other ion channels. We found that whole-cell hERG1 currents recorded in HEK293 cells were decreased upon neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2) co-expression. The amount of hERG1 channels in total HEK293 lysates and at the cell surface, as assessed by Western blot and biotinylation assays, respectively, were concomitantly decreased. Nedd4-2 and hERG1 interact via a PY motif located in the C-terminus of hERG1. Finally, we determined that Nedd4-2 mediates ubiquitylation of hERG1 and that deletion of this motif affects Nedd4-2-dependent regulation. These results suggest that ubiquitylation of the hERG1 protein by Nedd4-2, and its subsequent down-regulation, could represent an important mechanism for modulation of the duration of the human cardiac action potential.

Item Type:

Journal Article (Original Article)

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:

Albesa, Maxime; Grilo, Liliana Sintra and Abriel, Hugues

ISSN:

0022-2828

Publisher:

Elsevier

Funders:

[4] Swiss National Science Foundation

Projects:

[12] In vivo relevance of the PY and PDZ-domain binding motifs of the cardiac sodium channel Nav1.5 Official URL

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:20

Last Modified:

06 Dec 2013 13:27

Publisher DOI:

10.1016/j.yjmcc.2011.03.015

PubMed ID:

21463633

Web of Science ID:

000291580200012

URI:

https://boris.unibe.ch/id/eprint/6856 (FactScience: 211895)

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