Regulation of human cardiac potassium channels by full-length KCNE3 and KCNE4

Sci Rep. 2016 Dec 6:6:38412. doi: 10.1038/srep38412.

Abstract

Voltage-gated potassium (Kv) channels comprise pore-forming α subunits and a multiplicity of regulatory proteins, including the cardiac-expressed and cardiac arrhythmia-linked transmembrane KCNE subunits. After recently uncovering novel, N-terminally extended (L) KCNE3 and KCNE4 isoforms and detecting their transcripts in human atrium, reported here are their functional effects on human cardiac Kv channel α subunits expressed in Xenopus laevis oocytes. As previously reported for short isoforms KCNE3S and KCNE4S, KCNE3L inhibited hERG; KCNE4L inhibited Kv1.1; neither form regulated the HCN1 pacemaker channel. Unlike KCNE4S, KCNE4L was a potent inhibitor of Kv4.2 and Kv4.3; co-expression of cytosolic β subunit KChIP2, which regulates Kv4 channels in cardiac myocytes, partially relieved Kv4.3 but not Kv4.2 inhibition. Inhibition of Kv4.2 and Kv4.3 by KCNE3L was weaker, and its inhibition of Kv4.2 abolished by KChIP2. KCNE3L and KCNE4L also exhibited subunit-specific effects on Kv4 channel complex inactivation kinetics, voltage dependence and recovery. Further supporting the potential physiological significance of the robust functional effects of KCNE4L on Kv4 channels, KCNE4L protein was detected in human atrium, where it co-localized with Kv4.3. The findings establish functional effects of novel human cardiac-expressed KCNE isoforms and further contribute to our understanding of the potential mechanisms influencing cardiomyocyte repolarization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • CHO Cells
  • Cricetulus
  • Gene Expression Regulation*
  • Heart Atria / cytology
  • Heart Atria / metabolism
  • Heart Ventricles / cytology
  • Heart Ventricles / metabolism
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism
  • Kv Channel-Interacting Proteins / genetics
  • Kv Channel-Interacting Proteins / metabolism
  • Kv1.1 Potassium Channel / genetics
  • Kv1.1 Potassium Channel / metabolism
  • Mice
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Oocytes / cytology
  • Oocytes / metabolism
  • Potassium Channels / genetics
  • Potassium Channels / metabolism
  • Potassium Channels, Voltage-Gated / genetics*
  • Potassium Channels, Voltage-Gated / metabolism
  • Primary Cell Culture
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Subunits / genetics*
  • Protein Subunits / metabolism
  • Shal Potassium Channels / genetics
  • Shal Potassium Channels / metabolism
  • Signal Transduction
  • Transgenes
  • Xenopus laevis

Substances

  • HCN1 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • KCNE3 protein, human
  • KCNE4 protein, human
  • KCNIP2 protein, human
  • Kv Channel-Interacting Proteins
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Protein Isoforms
  • Protein Subunits
  • Shal Potassium Channels
  • Kv1.1 Potassium Channel