Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure
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,...
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eLife Sciences Publications Ltd
2022-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/77725 |
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| author | Xin Shen Jonas van den Brink Anna Bergan-Dahl Terje R Kolstad Einar S Norden Yufeng Hou Martin Laasmaa Yuriana Aguilar-Sanchez Ann P Quick Emil KS Espe Ivar Sjaastad Xander HT Wehrens Andrew G Edwards Christian Soeller William E Louch |
| author_facet | Xin Shen Jonas van den Brink Anna Bergan-Dahl Terje R Kolstad Einar S Norden Yufeng Hou Martin Laasmaa Yuriana Aguilar-Sanchez Ann P Quick Emil KS Espe Ivar Sjaastad Xander HT Wehrens Andrew G Edwards Christian Soeller William E Louch |
| author_sort | Xin Shen |
| collection | DOAJ |
| description | 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. |
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| language | English |
| last_indexed | 2024-04-12T16:36:43Z |
| publishDate | 2022-08-01 |
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| spelling | doaj.art-8009cf35beb44a249e475603ed9372722022-12-22T03:24:58ZengeLife Sciences Publications LtdeLife2050-084X2022-08-011110.7554/eLife.77725Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failureXin Shen0https://orcid.org/0000-0003-4429-8358Jonas van den Brink1Anna Bergan-Dahl2Terje R Kolstad3https://orcid.org/0000-0002-0589-5689Einar S Norden4Yufeng Hou5Martin Laasmaa6https://orcid.org/0000-0002-6663-6947Yuriana Aguilar-Sanchez7Ann P Quick8Emil KS Espe9Ivar Sjaastad10Xander HT Wehrens11Andrew G Edwards12Christian Soeller13https://orcid.org/0000-0002-9302-2203William E Louch14https://orcid.org/0000-0002-0511-6112Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, NorwaySimula Research Laboratory, Lysaker, NorwayInstitute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, NorwayInstitute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, NorwayInstitute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, NorwayInstitute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, NorwayInstitute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, NorwaySection 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 StatesSection 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 StatesInstitute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, NorwayInstitute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, NorwaySection 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 StatesSimula Research Laboratory, Lysaker, Norway; Department of Pharmacology, UC Davis, Davis, United StatesDepartment of Physiology, University of Bern, Bern, SwitzerlandInstitute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Centre for Cardiac Research, University of Oslo, Oslo, NorwayRyanodine 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.https://elifesciences.org/articles/77725calcium sparkscardiomyocytesryanodine receptorsheart failurephosphorylationβ-adrenergic stimulation |
| spellingShingle | Xin Shen Jonas van den Brink Anna Bergan-Dahl Terje R Kolstad Einar S Norden Yufeng Hou Martin Laasmaa Yuriana Aguilar-Sanchez Ann P Quick Emil KS Espe Ivar Sjaastad Xander HT Wehrens Andrew G Edwards Christian Soeller William E Louch Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure eLife calcium sparks cardiomyocytes ryanodine receptors heart failure phosphorylation β-adrenergic stimulation |
| title | Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure |
| title_full | Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure |
| title_fullStr | Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure |
| title_full_unstemmed | Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure |
| title_short | Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure |
| title_sort | prolonged β adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure |
| topic | calcium sparks cardiomyocytes ryanodine receptors heart failure phosphorylation β-adrenergic stimulation |
| url | https://elifesciences.org/articles/77725 |
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