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Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure.
- Source :
-
ELife [Elife] 2022 Aug 01; Vol. 11. Date of Electronic Publication: 2022 Aug 01. - Publication Year :
- 2022
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Abstract
- Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that 'dispersion' of RyR clusters disrupts Ca <superscript>2+</superscript> 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 <superscript>2+</superscript> /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 <superscript>2+</superscript> spark fidelity and magnitude, and slowed release kinetics from Ca <superscript>2+</superscript> 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 <superscript>2+</superscript> waves. However, during HF, RyR dispersion was linked to impaired Ca <superscript>2+</superscript> 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.<br />Competing Interests: XS, Jv, AB, TK, EN, YH, ML, YA, AQ, EE, IS, XW, AE, CS, WL No competing interests declared<br /> (© 2022, Shen et al.)
- Subjects :
- Adrenergic Agents metabolism
Adrenergic Agents pharmacology
Animals
Calcium metabolism
Calcium Signaling physiology
Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism
Cyclic AMP-Dependent Protein Kinases metabolism
Homeostasis
Mice
Myocytes, Cardiac metabolism
Phosphorylation
Rats
Heart Failure metabolism
Ryanodine Receptor Calcium Release Channel metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 11
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 35913125
- Full Text :
- https://doi.org/10.7554/eLife.77725