TY - JOUR
T1 - SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias
AU - Haron-Khun, Shiraz
AU - Weisbrod, David
AU - Bueno, Hanna
AU - Yadin, Dor
AU - Behar, Joachim
AU - Peretz, Asher
AU - Binah, Ofer
AU - Hochhauser, Edith
AU - Eldar, Michael
AU - Yaniv, Yael
AU - Arad, Michael
AU - Attali, Bernard
N1 - Publisher Copyright:
© 2017 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - cardiac arrhythmia
KW - catecholaminergic polymorphic ventricular tachycardia
KW - pacemaker
KW - potassium channel
KW - SK4
UR - http://www.scopus.com/inward/record.url?scp=85013439293&partnerID=8YFLogxK
U2 - 10.15252/emmm.201606937
DO - 10.15252/emmm.201606937
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SN - 1757-4676
VL - 9
SP - 415
EP - 429
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 4
ER -