KCNE2 modulates cardiac L-type Ca(2+) channel

J Mol Cell Cardiol. 2014 Jul;72:208-18. doi: 10.1016/j.yjmcc.2014.03.013. Epub 2014 Mar 26.


KCNE2 plays an important role in maintaining cardiac electrical stability. Mutations in KCNE2 have been linked to long-QT syndrome (LQT6) and atrial fibrillation/short QT syndrome. It has been suggested that KCNE2 has the most promiscuity of function which can interact with multiple-subunits of voltage-dependent cation channels and modulate their functions. However, whether KCNE2 regulates voltage-dependent L-type Ca(2)(+) channel (LCC) remains unknown. This study investigated the possible role of KCNE2 in regulating cardiac LCCs and the pathophysiological relevance of this regulation. We found that overexpression of KCNE2 in Sprague-Dawley rat cardiomyocytes decreased L-type Ca(2+)current (ICa,L), whereas KCNE2 knockdown by RNA interference increased ICa,L. Upregulation of KCNE2 caused a slight positive shift of the voltage-dependent activation and a negative shift of the steady-state voltage-dependent inactivation, and slowed the recovery from inactivation of ICa,L, while knockdown of KCNE2 had the contrary effects. Similar regulation of ICa,L magnitude had been observed in transfected HEK 293 cells. Coimmunoprecipitation and colocalization assays in both cardiomyocytes and the transfected cell line suggest that Cav1.2 physically interacted with KCNE2. Deletion of the N-terminal inhibitory module (NTI) of Cav1.2 results in the large loss of KCNE2 regulation of ICa,L and interaction with Cav1.2. Furthermore, we found that the familial atrial fibrillation related KCNE2 mutation R27C enhanced the effect of KCNE2 on suppressing ICa,L. Taken together, our findings indicate that KCNE2 modulates ICa,L by regulating NTI function of Cav1.2. The KCNE2 mutation R27C may induce familial atrial fibrillation partially through enhancing the suppression of ICa,L.

Keywords: Ca(v)1.2; Familial atrial fibrillation; KCNE2; KCNE2 mutation; L-type Ca(2+) current.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Calcium / metabolism*
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Gene Expression Regulation
  • HEK293 Cells
  • Heart Ventricles / cytology
  • Heart Ventricles / metabolism*
  • Humans
  • Mutation
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Patch-Clamp Techniques
  • Potassium Channels, Voltage-Gated / antagonists & inhibitors
  • Potassium Channels, Voltage-Gated / genetics
  • Potassium Channels, Voltage-Gated / metabolism*
  • Primary Cell Culture
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • Calcium Channels, L-Type
  • KCNE2 protein, rat
  • L-type calcium channel alpha(1C)
  • Potassium Channels, Voltage-Gated
  • RNA, Small Interfering
  • Calcium