Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
Jonas van den Brink
Simula Research Laboratory, Lysaker, Norway
Anna Bergan-Dahl
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
Einar S Norden
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
Yufeng Hou
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
Yuriana Aguilar-Sanchez
Section of Cardiology, Departments of Medicine and Pediatrics, Baylor College of Medicine, Houston, United States; Department of Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States
Ann P Quick
Section of Cardiology, Departments of Medicine and Pediatrics, Baylor College of Medicine, Houston, United States; Department of Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States
Emil KS Espe
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
Ivar Sjaastad
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
Xander HT Wehrens
Section of Cardiology, Departments of Medicine and Pediatrics, Baylor College of Medicine, Houston, United States; Department of Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States
Andrew G Edwards
Simula Research Laboratory, Lysaker, Norway; Department of Pharmacology, UC Davis, Davis, United States
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, Norway
Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that ‘dispersion’ of RyR clusters disrupts Ca2+ homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged β-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hr triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR. A similar role of protein kinase A (PKA) in promoting RyR cluster fragmentation was established by employing PKA activation or inhibition. Progressive cluster dispersion was linked to declining Ca2+ spark fidelity and magnitude, and slowed release kinetics from Ca2+ propagation between more numerous RyR clusters. In healthy cells, this served to dampen the stimulatory actions of β-adrenergic stimulation over the longer term and protect against pro-arrhythmic Ca2+ waves. However, during HF, RyR dispersion was linked to impaired Ca2+ release. Thus, RyR localization and function are intimately linked via channel phosphorylation by both CaMKII and PKA, which, while finely tuned in healthy cardiomyocytes, underlies impaired cardiac function during pathology.
