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

Autor: Asher Peretz, Bernard Attali, Yael Yaniv, Michael Eldar, Edith Hochhauser, Joachim Behar, Ofer Binah, Shiraz Haron-Khun, Michael Arad, Dor Yadin, Hanna Bueno, David Weisbrod
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Agonist
medicine.medical_specialty
medicine.drug_class
030204 cardiovascular system & hematology
Catecholaminergic polymorphic ventricular tachycardia
Cardiovascular System
03 medical and health sciences
cardiac arrhythmia
0302 clinical medicine
Internal medicine
SK4
Medicine
Animals
Calsequestrin
Humans
Channel blocker
Myocytes
Cardiac
Gene Knock-In Techniques
Induced pluripotent stem cell
Research Articles
Cells
Cultured
Mice
Knockout
catecholaminergic polymorphic ventricular tachycardia
business.industry
Sinoatrial node
Cardiac arrhythmia
medicine.disease
Intermediate-Conductance Calcium-Activated Potassium Channels
Embryonic stem cell
Potassium channel
pacemaker
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Tachycardia
Ventricular
Molecular Medicine
Genetics
Gene Therapy & Genetic Disease
business
Research Article
potassium channel
Zdroj: EMBO Molecular Medicine
ISSN: 1757-4684
1757-4676
Popis: 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 Ca 2+ 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 Ca 2+ ‐activated K + channels in adult pacemaker function, making them promising therapeutic targets for the treatment of cardiac ventricular arrhythmias such as CPVT.
Databáze: OpenAIRE
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