Stretch-activated two-pore-domain (K2P) potassium channels in the heart: Focus on atrial fibrillation and heart failure

Prog Biophys Mol Biol. 2017 Nov;130(Pt B):233-243. doi: 10.1016/j.pbiomolbio.2017.05.004. Epub 2017 May 16.

Abstract

Two-pore-domain potassium (K2P) channels modulate cellular excitability. The significance of stretch-activated cardiac K2P channels (K2P2.1, TREK-1, KCNK2; K2P4.1, TRAAK, KCNK4; K2P10.1, TREK-2, KCNK10) in heart disease has not been elucidated in detail. The aim of this work was to assess expression and remodeling of mechanosensitive K2P channels in atrial fibrillation (AF) and heart failure (HF) patients in comparison to murine models. Cardiac K2P channel levels were quantified in atrial (A) and ventricular (V) tissue obtained from patients undergoing open heart surgery. In addition, control mice and mouse models of AF (cAMP-response element modulator (CREM)-IbΔC-X transgenic animals) or HF (cardiac dysfunction induced by transverse aortic constriction, TAC) were employed. Human and murine KCNK2 displayed highest mRNA abundance among mechanosensitive members of the K2P channel family (V > A). Disease-associated K2P2.1 remodeling was studied in detail. In patients with impaired left ventricular function, atrial KCNK2 (K2P2.1) mRNA and protein expression was significantly reduced. In AF subjects, downregulation of atrial and ventricular KCNK2 (K2P2.1) mRNA and protein levels was observed. AF-associated suppression of atrial Kcnk2 (K2P2.1) mRNA and protein was recapitulated in CREM-transgenic mice. Ventricular Kcnk2 expression was not significantly altered in mouse models of disease. In conclusion, mechanosensitive K2P2.1 and K2P10.1 K+ channels are expressed throughout the heart. HF- and AF-associated downregulation of KCNK2 (K2P2.1) mRNA and protein levels suggest a mechanistic contribution to cardiac arrhythmogenesis.

Keywords: Atrial fibrillation; Heart failure; Stretch-activated ion channels; TREK-1; Two-pore-domain potassium channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Atrial Fibrillation / genetics
  • Atrial Fibrillation / metabolism*
  • Biomechanical Phenomena
  • Down-Regulation
  • Female
  • Heart Failure / genetics
  • Heart Failure / metabolism*
  • Humans
  • Male
  • Mechanical Phenomena*
  • Middle Aged
  • Models, Molecular
  • Myocardium / metabolism*
  • Potassium Channels, Tandem Pore Domain / chemistry
  • Potassium Channels, Tandem Pore Domain / genetics
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Protein Conformation
  • Protein Transport
  • Up-Regulation

Substances

  • KCNK1 protein, human
  • Potassium Channels, Tandem Pore Domain