title: SK4 K+channels are therapeutic targets for the treatment of cardiac arrhythmias.
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 vivoECG 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.
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel.
authors.forename: Shiraz
authors.initials: S
authors.lastname: Haron-Khun
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Weisbrod
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bueno
authors.affiliation: Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel.
authors.forename: Dor
authors.initials: D
authors.lastname: Yadin
authors.affiliation: Laboratory of Bioenergetic and Bioelectric Systems, Biomedical Engineering Faculty, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Joachim
authors.initials: J
authors.lastname: Behar
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Asher
authors.initials: A
authors.lastname: Peretz
authors.affiliation: Department of Physiology, Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Binah
authors.affiliation: The Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel.
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
authors.affiliation: Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Eldar
authors.affiliation: Laboratory of Bioenergetic and Bioelectric Systems, Biomedical Engineering Faculty, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Yaniv
authors.affiliation: Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel michael.arad@sheba.health.gov.il battali@post.tau.ac.il.
authors.forename: Michael
authors.identifier: 0000-0003-3723-7493
authors.initials: M
authors.lastname: Arad
authors.affiliation: Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel michael.arad@sheba.health.gov.il battali@post.tau.ac.il.
authors.forename: Bernard
authors.identifier: 0000-0003-1066-7047
authors.initials: B
authors.lastname: Attali
mesh_terms: D000818:Animals; D002155:Calsequestrin / Q000235:genetics; D002478:Cells, Cultured; D055879:Gene Knock-In Techniques; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology*; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: C443109:CASQ2 protein, human; D002155:Calsequestrin; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; C496925:Kcnn4 protein, mouse
keywords: SK4; cardiac arrhythmia; catecholaminergic polymorphic ventricular tachycardia; pacemaker; potassium channel