RGD Reference Report - Cell surface expression of human ether-a-go-go-related gene (hERG) channels is regulated by caveolin-3 protein via the ubiquitin ligase Nedd4-2. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Cell surface expression of human ether-a-go-go-related gene (hERG) channels is regulated by caveolin-3 protein via the ubiquitin ligase Nedd4-2.

Authors: Guo, J  Wang, T  Li, X  Shallow, H  Yang, T  Li, W  Xu, J  Fridman, MD  Yang, X  Zhang, S 
Citation: Guo J, etal., J Biol Chem. 2012 Sep 28;287(40):33132-41. Epub 2012 Aug 9.
RGD ID: 8553349
Pubmed: (View Article at PubMed) PMID:22879586
DOI: Full-text: DOI:10.1074/jbc.M112.389643

The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (I(Kr)) which plays an important role in cardiac repolarization. A reduction or increase in hERG current can cause long or short QT syndrome, respectively, leading to fatal cardiac arrhythmias. The channel density in the plasma membrane is a key determinant of the whole cell current amplitude. To gain insight into the molecular mechanisms for the regulation of hERG density at the plasma membrane, we used whole cell voltage clamp, Western blotting, and immunocytochemical methods to investigate the effects of an integral membrane protein, caveolin-3 (Cav3) on hERG expression levels. Our data demonstrate that Cav3, hERG, and ubiquitin-ligase Nedd4-2 interact with each other and form a complex. Expression of Cav3 thus enhances the hERG-Nedd4-2 interaction, leading to an increased ubiquitination and degradation of mature, plasma-membrane localized hERG channels. Disrupting Nedd4-2 interaction with hERG by mutations eliminates the effects of Cav3 on hERG channels. Knockdown of endogenous Cav3 or Nedd4-2 in cultured neonatal rat ventricular myocytes using siRNA led to an increase in native I(Kr). Our data demonstrate that hERG expression in the plasma membrane is regulated by Cav3 via Nedd4-2. These findings extend our understanding of the regulation of hERG channels and cardiac electrophysiology.

Annotation

Gene Ontology Annotations    

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Cav3  (caveolin 3)
Kcnh2  (potassium voltage-gated channel subfamily H member 2)
Nedd4l  (NEDD4 like E3 ubiquitin protein ligase)


Additional Information