KCNE2 protein is more abundant in ventricles than in atria and can accelerate hERG protein degradation in a phosphorylation-dependent manner

Am J Physiol Heart Circ Physiol. 2012 Feb 15;302(4):H910-22. doi: 10.1152/ajpheart.00691.2011. Epub 2011 Dec 16.


KCNE2 functions as an auxiliary subunit in voltage-gated K and HCN channels in the heart. Genetic variations in KCNE2 have been linked to long QT syndrome. The underlying mechanisms are not entirely clear. One of the issues is whether KCNE2 protein is expressed in ventricles. We use adenovirus-mediated genetic manipulations of adult cardiac myocytes to validate two antibodies (termed Ab1 and Ab2) for their ability to detect native KCNE2 in the heart. Ab1 faithfully detects native KCNE2 proteins in spontaneously hypertensive rat and guinea pig hearts. In both cases, KCNE2 protein is more abundant in ventricles than in atria. In both ventricular and atrial myocytes, KCNE2 protein is preferentially distributed on the cell surface. Ab1 can detect a prominent KCNE2 band in human ventricular muscle from nonfailing hearts. The band intensity is much fainter in atria and in failing ventricles. Ab2 specifically detects S98 phosphorylated KCNE2. Through exploring the functional significance of S98 phosphorylation, we uncover a novel mechanism by which KCNE2 modulates the human ether-a-go-go related gene (hERG) current amplitude: by accelerating hERG protein degradation and thus reducing the hERG protein level on the cell surface. S98 phosphorylation appears to be required for this modulation, so that S98 dephosphorylation leads to an increase in hERG/rapid delayed rectifier current amplitude. Our data confirm that KCNE2 protein is expressed in the ventricles of human and animal models. Furthermore, KCNE2 can modulate its partner channel function not only by altering channel conductance and/or gating kinetics, but also by affecting protein stability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Dogs
  • Female
  • Guinea Pigs
  • Heart Atria / cytology
  • Heart Atria / metabolism*
  • Heart Ventricles / cytology
  • Heart Ventricles / metabolism*
  • Humans
  • Male
  • Models, Animal
  • Molecular Sequence Data
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Patch-Clamp Techniques
  • Phosphorylation
  • Potassium Channels, Voltage-Gated / analysis
  • Potassium Channels, Voltage-Gated / metabolism*
  • Proteolysis*
  • Rats
  • Rats, Inbred SHR
  • Shal Potassium Channels
  • Trans-Activators / metabolism*
  • Transcriptional Regulator ERG


  • ERG protein, human
  • KCNE2 protein, human
  • KCNE2 protein, rat
  • Potassium Channels, Voltage-Gated
  • Shal Potassium Channels
  • Trans-Activators
  • Transcriptional Regulator ERG