Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure.

Autor:	Shen X; 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., van den Brink J; Simula Research Laboratory, Lysaker, Norway., Bergan-Dahl A; 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., Kolstad TR; 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., Norden ES; 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., Hou Y; 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., Laasmaa M; 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., Aguilar-Sanchez Y; 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., Quick AP; 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., Espe EKS; 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., Sjaastad I; 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., Wehrens XHT; 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., Edwards AG; Simula Research Laboratory, Lysaker, Norway.; Department of Pharmacology, UC Davis, Davis, United States., Soeller C; Department of Physiology, University of Bern, Bern, Switzerland., Louch WE; 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.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 Aug 01; Vol. 11. Date of Electronic Publication: 2022 Aug 01.
DOI:	10.7554/eLife.77725
Abstrakt:	Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that 'dispersion' of RyR clusters disrupts Ca 2+ 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 Ca 2+ /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 Ca 2+ spark fidelity and magnitude, and slowed release kinetics from Ca 2+ 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 Ca 2+ waves. However, during HF, RyR dispersion was linked to impaired Ca 2+ 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. Competing Interests: XS, Jv, AB, TK, EN, YH, ML, YA, AQ, EE, IS, XW, AE, CS, WL No competing interests declared (© 2022, Shen et al.)
Databáze:	MEDLINE
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