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 hu...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606937 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shiraz Haron‐Khun |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f81d60e628cd448aa9f2afc49e1e9d69 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-f81d60e628cd448aa9f2afc49e1e9d692025-08-20T03:43:29ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-02-019441542910.15252/emmm.201606937SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmiasShiraz Haron‐Khun0David Weisbrod1Hanna Bueno2Dor Yadin3Joachim Behar4Asher Peretz5Ofer Binah6Edith Hochhauser7Michael Eldar8Yael Yaniv9Michael Arad10Bernard Attali11Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv UniversityDepartment of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv UniversityDepartment of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv UniversityLeviev Heart Center, Sheba Medical Center, Tel HashomerLaboratory of Bioenergetic and Bioelectric Systems, Biomedical Engineering Faculty, Technion—Israel Institute of TechnologyDepartment of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv UniversityDepartment of Physiology, Ruth & Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of TechnologyThe Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Rabin Medical Center, Tel Aviv UniversityLeviev Heart Center, Sheba Medical Center, Tel HashomerLaboratory of Bioenergetic and Bioelectric Systems, Biomedical Engineering Faculty, Technion—Israel Institute of TechnologyLeviev Heart Center, Sheba Medical Center, Tel HashomerDepartment of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv UniversityAbstract 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.https://doi.org/10.15252/emmm.201606937cardiac arrhythmiacatecholaminergic polymorphic ventricular tachycardiapacemakerpotassium channelSK4 |
| spellingShingle | 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 SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias EMBO Molecular Medicine cardiac arrhythmia catecholaminergic polymorphic ventricular tachycardia pacemaker potassium channel SK4 |
| title | SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias |
| title_full | SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias |
| title_fullStr | SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias |
| title_full_unstemmed | SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias |
| title_short | SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias |
| title_sort | sk4 k channels are therapeutic targets for the treatment of cardiac arrhythmias |
| topic | cardiac arrhythmia catecholaminergic polymorphic ventricular tachycardia pacemaker potassium channel SK4 |
| url | https://doi.org/10.15252/emmm.201606937 |
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