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

Shiraz Haron-Khun, David Weisbrod, Hanna Bueno, Dor Yadin, Joachim Behar, Asher Peretz, Ofer Binah, Edith Hochhauser, Michael Eldar, Yael Yaniv, Michael Arad*, Bernard Attali

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish
Pages (from-to)415-429
Number of pages15
JournalEMBO Molecular Medicine
Volume9
Issue number4
DOIs
StatePublished - 1 Apr 2017

Funding

FundersFunder number
Israel Science Foundation2092/14, 763/10, ISF 1215/13, ISF 292/13

    Keywords

    • SK4
    • cardiac arrhythmia
    • catecholaminergic polymorphic ventricular tachycardia
    • pacemaker
    • potassium channel

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