SK4 K + channels are therapeutic targets for the treatment of cardiac arrhythmias

EMBO Mol Med. 2017 Apr;9(4):415-429. doi: 10.15252/emmm.201606937.

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-provoked ventricular arrhythmia, which also manifests sinoatrial node (SAN) dysfunction. We recently showed that SK4 calcium-activated potassium channels are important for automaticity of cardiomyocytes derived from human embryonic stem cells. Here SK4 channels were identified in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from healthy and CPVT2 patients bearing a mutation in calsequestrin 2 (CASQ2-D307H) and in SAN cells from WT and CASQ2-D307H knock-in (KI) mice. TRAM-34, a selective blocker of SK4 channels, prominently reduced delayed afterdepolarizations and arrhythmic Ca2+ transients observed following application of the β-adrenergic agonist isoproterenol in CPVT2-derived hiPSC-CMs and in SAN cells from KI mice. Strikingly, in vivo ECG recording showed that intraperitoneal injection of the SK4 channel blockers, TRAM-34 or clotrimazole, greatly reduced the arrhythmic features of CASQ2-D307H KI and CASQ2 knockout mice at rest and following exercise. This work demonstrates the critical role of SK4 Ca2+-activated K+ channels in adult pacemaker function, making them promising therapeutic targets for the treatment of cardiac ventricular arrhythmias such as CPVT.

Keywords: SK4; cardiac arrhythmia; catecholaminergic polymorphic ventricular tachycardia; pacemaker; potassium channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calsequestrin / genetics
  • Cells, Cultured
  • Gene Knock-In Techniques
  • Humans
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Mice, Knockout
  • Myocytes, Cardiac / physiology*
  • Tachycardia, Ventricular / physiopathology*

Substances

  • CASQ2 protein, human
  • Calsequestrin
  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • KCNN4 protein, human
  • Kcnn4 protein, mouse

Supplementary concepts

  • Polymorphic catecholergic ventricular tachycardia